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This article isThis article by protected copyright. All rights reserved. 10.1002/1873doi: differences to lead between the this version and Version copyediting, paginationbeen throughthe andproofreadingtypesetting, process,may which Accepted This article acceptedhas been for publication andundergone fullpeer review buthasnot phylogenetic corresponds system numbering the and including non (MYH9, isoforms three but muscle, cardiac class processes. movement, and force generate and filaments actin along translocate to hydrolysis ATP by powered are proteins motor Myosin Introduction regulating Cmediate the Thus, MYO6. of conformation folded inactive the controls also cytoskeleton. septin highlight whichcomplexes, protein functionally large several including interactome MYO6 wider the identify to isofo MYO6 cardiomyopathy, deafness, including NDP52 pathologies of as such partners binding direct variety a to diseas neurodegenerative linked is in MYO6 humans of overexpression or loss Indeed, processes. biological of number a in important filaments. actin of ends minus the actin unique are (MYO6) VI class of Myosins Abstract Article Keywords: Building, Hills C Road,Cambridge InstituteCambridge Research, forMedical University ofCambridge, TheKeithPeters Janeska The Corresponding author mail type Article :Review DateAccepted 10 : Revised Date:07 DateReceived 01 : - MYO6 muscle cells muscle - II myosins named MYH1 to MYH15. Most of these are expressed in smooth, skeletal or skeletal smooth, in expressed are these of Most MYH15. to MYH1 named myosins II
and also D also and
s cargo recognition and binding, cargobinding, s and recognition J. :
eight class I myosin genes, MYO1A to MYO1H) encode encode MYO1H) to MYO1A genes, myosin I class eight
De Jonge, Jonge, De
cytoskeletal track dynamics. The human genome contains 39 myosin genes; 15 genes code for “conventional” “conventional” for code genes 15 genes; myosin 39 contains genome human The interactome myosin, actin, BioID, cargo rms along the endocytic pathway endocytic the along rms : comparison
(non ab - - - 3468.13486 - May Jun Jun 2, GIPC, TOM1 and LMTK2, which mediate distinct functions of different different of functionsdistinct mediate which LMTK2, and TOM1 GIPC, 2, Chris Interestingly - mu - - : 2019 2019 -
2019 selective selective motor scl topher es as well as cancer. cancer. as well as es f utpe uaytc organisms eukaryotic multiple of - id e
: myosin IIA, B or C) or B IIA, myosin
[email protected] the selective autophagy receptors optineurin, TAX1BP1 and TAX1BP1 optineurin, receptors autophagy selective the
B2 0XY, UK B , adaptor , atters, Susan Susan D.ArdenFolmaBuss and atters, the importance of importance the As the sole myosin with this directionality, it is critically critically is it directionality, this with myosin sole the As - binding, endocytosis, autophagybinding,
hc is which but -
cargo complexes fordi to the to - MYH10 and MYH14) and MYH10 binding not only triggers cargo attachment, but attachment, cargo triggers only not binding
- is based motor proteins that move cargo towards cargo move that proteins motor based . F also crucial for modul for crucial also unctional proteomics has recently been used used been recently has proteomics unctional This . The remaining 24 genes (MYO1 to MYO19 MYO19 to (MYO1 genes 24 remaining The . 12 different different 12
motn fr wd rne f dynamic of range wide a for important myosin myosin this myosin in regulating the acti the regulating in myosinthis of citethisarticle as Record.Please
interacts with a wide variety of of variety wide a with interacts [1] myosin classes established by by established classes myosin
verse are selectively expressed selectively are [2] “ unconventional
ating motor activity and and motor activity ating [3]
cellular processes -
. terminal tail domain tail terminal ysn o cas II, class of Myosins
- distinct multi distinct ”
myosins myosins n and n brought toyouby .
in - provided byApollo CORE This article isThis article by protected copyright. All rights reserved. cargo the in sites distinct to adaptors different li of combination a involve Overall, motifs. binding lipid MYO6 stabilise and affinity the complexes enhance can which chains, ubiquitin of variety a MYO6, to directly bind to shown motif binding lipid one and motifs binding unique dimerization induce to shown been has partners binding different with association however, monomer, a is vitro in MYO6 MYO6. of targeting oper MYO6 whether determine temporal may proteins and spatial precise for crucial situ in or domain screens, hybrid w domain, tail multi The [13] reported been has MYO6 of expression increased Fu loss. hearing and cardiomyopathy hypertrophic including pathologies of range mice In humansand inner andstereociliathe ear. microvilli in earl M a more like anchorthananactivetransportermolecular Furthermore unison. suggest and dimer a as acting when processive weakly be to ability its to points myosin this of gating moving molecu single and bulk [5] motion (insert “backwards” insert unique allow to orientation an into arm lever the an repositions of presence the reveals unique plus the towards move members family myosin All chains, length in varying region a domain, motor conserved highly a contain proteins motor Myosin transport. range short or functions tethering performing by cytokinesis or trafficking vesicle migration, cell cells. in forces contractile of generation and contraction muscle for essential filaments bipolar to form class only the are and discovered be to first the were myosins, conventional called also YO6 performs a wide range of range wide a performs YO6
Accepted Article. y endosomes, y
The kinetic and biophysical characteristics of this myosin have been well studied at the at studied well been have myosin this of characteristics biophysical and kinetic The [14]
and diversetail domains forcargoselection linkedtospecialized functions. myosin actin filaments approximately 110 approximately filaments actin In , making it a potential itapotential , making - functionality of MYO6 requires interaction with a host of binding partners via its via partners binding of host a with interaction requires MYO6 of functionality
con [21]
ht ogr ags f oeet rbby eur svrl ies cig in acting dimers several require probably movement of ranges longer that trast, the unconventional myosins fulfil diverse cellular roles cellular diverse fulfil myosins unconventional the trast, o class of s hich
native co native [22] on
proximity labelling proximity . MYO6 can also directly interact with membranes through its C its through membranes with interact directly also can MYO6 . ae en dniid sn a ait o apoce including approaches of variety a using identified been have -
in the presence of load or high ADP MYO6 has been shown to behave behave to shown been has MYO6 ADP high or load of presence the in 1) is located near the ATP binding site and modulates ATPase activity ATPase modulates and site binding ATP the near located is 1) clathrin coated structures at the plasma membrane and at the base of of base the at and membrane plasma the at structures coated clathrin including two adaptor binding domains, two ubiquitin binding regions regions binding ubiquitin two domains, binding adaptor two including le level le
that provides that
- VI immunoprecipitation, affinity chromatography using the MYO6 tail MYO6 the using chromatography affinity immunoprecipitation,
pid and protein binding protein and pid (MYO6)
( the e fgr 1 D). 1 figure see i early ofmarker development. cancer additional additional n vitro n (figure 1 B) B) 1 (figure specialized recent work has also suggested that binding might involve might binding that suggested also has work recent cellular positioning and function and positioning cellular [4]
bindings sites bindings and [15] .
h cytl tutr o te Y6 oo domain motor MYO6 the of structure crystal The - insert
have 140 nm/s 140 [16] [8] functions for example in membrane ruffles, on ruffles, membrane in example for functions ates in cells as a monomer or a dimer. Purified dimer. a or monomer a as cells in ates
-
binding tail, which can either be direct or via via or direct be either can which tail, binding Although most binding partners have been been have partners binding most Although [19]
[17] shown that shown (insert ;
in for
- [18] [20] [6] sequential or simultaneous binding of of binding simultaneous or sequential end of actin actin of end
many different different many up to six calmodulins or related light light related or calmodulins six to up
- [10]
[7] 2) . . Binding h ti domain tail The
[8] n h cnetr oan that domain converter the in MYO6 .
MYO6 mutations cause a widea MYO6 cause mutations
[9] n diin tee adaptor these addition, In
. these adaptor proteins is proteins adaptor these iaet, e filaments, (s) is a relatively slow motor slow relatively a is The duty cycle and weak weak and cycle duty The
of MYO6 of carcinoma
, for example, for , contains several several contains [5] xcept for xcept are are rthermore, rthermore, . s
second A - [11] - terminal likely to to likely adaptor yeast
neck [12] the the [9]
- in 2 -
This article isThis article by protected copyright. All rights reserved. protein G kinases, tyrosine receptor including receptors surface cell of number large a with interacts which GIPC1, of domain PDZ the to binds APPL1 terminus phospholipid mediate [30] and Rab5 GTPase ( small the for positive are which endosomes, T [18] and EPS15L1 PICALM, SYNJ1, ITSN1, AP2, as domain tail labelling proximity situ in Indeed, machinery. endocytic the of components receptors surface cell of tail cytoplasmic the to binding mediates that domain (PTB) binding phosphotyrosine a contains [28] the involves structures coated clathrin in clustering as well Na the of movement the facilitate thereby enterocytes of domain apical conductance transmembrane fibrosis cystic the of endocytosis in of loss Indeed, clathrin with domain The insert (NI) 21 (adding (LI) insert large a contain variants splice These pathway. endocytic the along steps at distinct roles specialised perform which tissues, and types cell different in expressed are MYO6 After membrane. plasma surface. the cell the to back recycled or degradation lysosomal for either in invaginations from vesicles receptor internalisation the of formation the initiate clathrin including described been have routes uptake parallel Several membrane. plasma receptors the surface from cell or nutrients basic of uptake the permits endocytosis of process The Diverse of roles C we Moreover, involved. are and they domainorganization which in processes cellular the and In tight chains ubiquitin A e is he ellular daptor Accepted Articlearticle, this , . MYO6
regulation and deactivationfor initiation eventually of recycling MYO6.and [31] and the clathrin adaptor clathrin the and fr of oform
-
functions ofMYO6 eitd noyoi, n hc te rti cahi ad soitd ma associated and clathrin protein the which in endocytosis, mediated ( the movement of sodium transporters in renal proximal tubule cells to allow allow to cells tubule proximal renal in transporters sodium of movement the leading to proteinuria proteinuria to leading CBD AP1 s mliucinl dpo poen otiig utpe oan that domains multiple containing protein adaptor multifunctional a is APPL1 . P
(see figure - splice variant containing splice rotein 31 amino acids), a small insert (SI) insert small a acids), amino 31 identified several proteins associated with clathrin with associated proteins several identified - ) coated pits or vesicles at the base of microvilli at the apical plasma membrane. plasma apical the at microvilli of base the at vesicles or pits coated
we is predominantly expressed in polarised epithelial cells, where it associ it where cells, epithelial polarised in expressed predominantly is MYO6
MYO6 MYO6 se iue 2) figure (see
discuss the molecular interactions between MYO6 and its binding partners binding its and MYO6 between interactions molecular the discuss P opoyoie neatn wt P dmi and domain PH with interacting hosphotyrosine -
1
expression expression otd is n endocytosis and pits coated
binding
) in thein endocytic pathway ihu ay inserts any without .
recent advancesrecent inour
- containing vesicles are delivered to early endosomes and sorted sorted endosomes and deliveredto early are vesicles containing ,
I adto, a2 features Dab2 addition, In .
as well as in as well as
and allow in allow and Dab2 Ti cmlx rcs o motor of process complex This . LI splice variant splice LI [23] in + /H the the knock out mice ( mice out knock the
(
D + [24]
is exchanger down the microvillus in intestinal cells intestinal in microvillus the down exchanger large insert large insert ab
teraction with many signalling receptors. At its C its At receptors. signalling many with teraction the led [25] (NI) FCHO2 that FCHO2 -
, which , uptake of the megalin the of uptake 2 . (adding 9 amino acids), both LI and SI or no no or SI and LI both acids), amino 9 (adding
) understanding ofunderstanding regulation. MYO6
s rsn o a ust f eihrl early peripheral of subset a on present is
[15] Interestingly,
(LI) [26] . constitutes The atthebeginning of
Snell’s waltzer m waltzer Snell’s
[27] are
endocytic adaptor protein adaptor endocytic eea bnig ie fr other for sites binding several
. linked to linked MYO6 - MYO6 - mediated endocytosis such such endocytosis mediated cargo recognition requires requires recognition cargo
regulator (CFTR) from the from (CFTR) regulator a clathrin a h Rab5 the - -
coupled receptors and receptors coupled receptor in the kidney the in receptor Four splice isoforms of of isoforms splice Four L
agtn t clathrin to targeting eucine eucine MYO6 has been shown to to shown been has ice) review -
using the MYO6 the using binding domain binding
effector
causes defects causes
Z through Dab2 through cargo ipper
the MYO6 MYO6 the -
binding binding chinery 1 , APPL1 APPL1
) Dab2
ates ates [29] , as , - - ,
This article isThis article by protected copyright. All rights reserved. polaris in domain membrane plasma basolateral the to proteins transmembrane synthesized newly waltzer exocytosis constitutive in Snell’s the from isolated s Golgi in reduction significant fibroblasts using studies Functional comple Golgi the around cell. the plasma from release the or incorporation to delivery for sorted and processed are they where complex, are reticulum endoplasmic the role role its to addition In Fun LMTK2 or whether whether known not is it present endocytic defects regulate and cancer neurodegeneration, to to function linked and are shown expression LMTK2 been in Changes apoptosis. has and signalling it as well althoughas trafficking, kinases other to compared protein compartment recycling the into endosomes in participate to appears it where endosomes, positive kinase Another necrosis factor unclear, still is complex of function exact the Although endosomes. early on present ( lysosoma for vesicles destined intraluminal cargo ubiquitinated of sorting ESCRT contain proteins Both p Additional early endosome andretrograde motility movement of receptors internalised coupled GIPC1, of complex LARG, tripartite a identified experiments proximity situ in recent endosomes of clustering cortical extreme causes filaments actin of end plus the cell perinuclearof the region the the that findings the by supported also is endosomes signalling non a movement of expression since network, ea translocate APPL1 prote transmembrane other Toll Accepted Articlerotein
ctionsof premature maturation and displacement of APPL1 endosomes from the cell cortex in cortex cell the from endosomes APPL1 of displacement and maturation premature
in I nteracting - -
d pteil el ad o h laig de f irtr cells migratory of edge leading the to and cells epithelial ed which is which sbnt Hs n STAM and Hrs subunits 0 positive positive LMTK2 cargo transport in the secretory pathway. secretory the in transport cargo 1)
receptors may link Rho signalling to remodelling of the actin cortex to regulate regulate to cortex actin the of remodelling to signalling Rho link may receptors MYO6
and the related TOM1L2 related the and MYO6 [33] MYO6
rly endosomes away from the plasma membrane through the cortical actin cortical the through membrane plasma the from away endosomes rly - ( alpha signalling andtrafficking alpha signalling L
a GEF for RHO GTPases. LARG activation downstream of specific G protein G specific of downstream activation LARG GTPases. RHO for GEF a al endosomes early adaptor in the endocytic pathway is the transmembrane serine/threonine transmembrane the is pathway endocytic the in adaptor [31] e P
m rotein) rotein) dpo protein adaptor MYO6
ur in the exocyticin the pathway
[34]
[37] in the endocytic pathway endocytic the in
T ubiquitin a yrosine TOM1 .
.
mediates thecellular localisationmediates andtrafficking of this kinase. and/or x
[45] A crucial role for role crucial A Targeting of TOM1/L2 to endosomes involves binding to binding involves endosomes to TOM1/L2 of Targeting
[44] ins. GIPC ins. . ize compared to compared ize
Furthermore, Furthermore, has been implicated in regulating interleukin regulating in implicated been has
K
[45] [35] inase
endofin Ti fml o poen pas n motn rl in role important an plays proteins of family This . [32] - s rnpre i tblrvsclr ares o h Golgi the to carriers tubular/vesicular in transported MYO6 idn GT oan n a H domain VHS a and domain GAT binding
( n hs ery endosomes early these on
T
also binds directly to MYO6 and MYO6 to directly binds also and expressionmutant and of a n t vsce coe o h pam membrane plasma the to close vesicles to and arget arget Te GIPC1 The . - 2 functional functional MYO6 )
, [40] activity is regulated through phosphorylation by by phosphorylation through regulated is activity which contains a contains which
MYO6 O
[29] MYO6
f . This kinase colocalises with colocalises kinase This . [38] localises to vesicles in the perinuclear region region perinuclear the in vesicles to localises wild type wild , M
MYO6 . Little is kn is Little . yb1
MYO6 [39] - in the spatial organisation of the APPL1 the of organisation spatial the in In this pathway this In
MYO6 is required for the polarised delivery of of delivery polarised the for required is
L
in spermatogenesis in . ike appears to play a similarly important similarly a play to appears
the dgaain no ae endocytic late into degradation l fibroblasts, combined with combined fibroblasts,
io mtn inhibit mutant rigor 2 complex has been suggested to to suggested been has complex
the Membrane Trafficking Protein) Trafficking Membrane sorting of receptors from early early from receptors of sorting FYVE own about the function of this this of function the about own TOM1
depletion of depletion are MYO6
domain that binds PI(3)P binds that domain , proteins synthesized at synthesized proteins ,
TOM1 recruit and the and [46]
that moves towards that
[41] [47] os rva a reveal mouse
MYO6
(
s smlr o the to similar , [18] T MYO6 - ebae for membrane
1 and tumour and 1 this myosin this arget arget MYO6
Te oe of role The . s
[42] [36]
. MYO6 endosome
on Rab5 on
. Finally, . a defect defect a leads to leads [43]
o / TOLLIP TOLLIP f TOM1
[16] M
and and . the the
yb yb At At to - - . .
This article isThis article by protected copyright. All rights reserved. healthy the re the from mitophagy for role for novel This network. destined mitochondria dysfunctional isolating thereby NDP52 and domain TAX1BP1 optineurin, on depend not does autophagy via during Furthermore, as such pathogens In addition, autophagosome fusionandmaturation mecha of complex ternary a that model endosome binding the and by receptors the autophagy of binding autophagosomes simultaneous allows domains binding two of these between distance the that surface outer sites distinct to the bind TOM1 to myosin to simultaneously this of recruitment without objects cytosolic ubiquitinated re of autophagy capture the of function dual a with consistent than the with overlaps B ( NDP52 optineurin, receptors, autophagy obj ubiquitinated the autophagosome. capturing thereby and membranes autophagosomal associated t receptors autophagy LC3 with interact selective typically receptors autophagy The domain. binding ubiquitin by recognised is which tag, ubiquitin a protein with as such proteasome the via degraded for be typically aremarked objects organellesandinvading pathogens.These damaged aggregates, to large required too are that machinery objects cytosolic essential non a deliver in starvation of conditions to under believed are autophagosome which endosomes, wi fusion by early formed are amphisomes closure, autophagosome After autophagosomes. double large in sequestered are which components, cytosolic of an is Autophagy MYO6 interactions withother proteins EN c via tethering regulated dependent cortex actin the to granules secretory membrane secretion binding optineurin established an MYO6 inding
Accepted Article that proteins scaffolding A/VASP the -
im for nism integration mitochondria into of thefunctionalmitochondrialnetwork. damaged and autophagy in the secretory pathway is closely linked to optineurin and the small GTPase Rab8, Rab8, GTPase small the and optineurin to linked closely is pathway secretory the in
[53] P rotein rotein involve neato o te uohg rcpo wt ubiquitin with receptor autophagy the of interaction
MYO6 [48] P .
oen 1A/1B rotein MYO6 ,
MYO6 .
the
essential lysosomal degradation pathway for the breakdown and recycling recycling and breakdown the for pathway degradation lysosomal essential – 1
n ersceoy el te ml insert small the cells neurosecretory In
MYO6 secretory vesicle fusion and possibly fusion pore opening at the plasma plasma the at opening pore fusion possibly and fusion vesicle secretory Y6 a be son o id iety o he o te well the of three to directly bind to shown been has MYO6
). MYO6 has a crucial a has lysosome fusion. Autophagy maintains cellular homeostasis and growth growth and homeostasis cellular maintains Autophagy fusion. lysosome
ehrn o edsms o uohgsms o aiiae endosome facilitate to autophagosomes to endosomes of tethering
nue te omto o atn ae aon dmgd mitochondria damaged around cages actin of formation the induces mitophagy,
amnla typhimurium Salmonella n l tre uohg rcpos h ubiquitin the receptors autophagy three all In
is selectively recruited to damaged mitochondria damaged to recruited selectively is of these secretory granules to the cortical actin network involves involves network actin cortical the to granules secretory these of
binding site binding and autophagosome and -
L in the in ight MYO6
role inrole
[49, 50] h ptwy for pathway the C MYO6
MYO6
hain is unique to mitophagy, where the actin cages prevent cages actin the where mitophagy, to unique is , h , ate. The partner. are involved in actin polymerisation in addition to to addition in polymerisation actin in involved are xenophagy for the autophagy the for xenophagy
owever, [30] . -
eetv poes Ti ptwy lo agt lar targets also pathway This process. selective T ,
3 N CBD - ) nhr T anchor . uclear tigrn te erimn o LC3 of recruitment the triggering ,
OM
- associated L associated ; p ;
the 1 and the autophagy receptors provides a a provides receptors autophagy the and 1 rm h ctsl f netd cells infected of cytosol the from ull down experiments have demonstrated have experiments down ull D
removal of removal binding of TAX1BP1 to TAX1BP1 of binding functions ot MYO6 OM ceptors: first in the recognition and and recognition the in first ceptors: P
1 rotein
-
u rqie is ubiquitin its requires but Src phosphorylation phosphorylation Src
C3. [52] participation and second in the the in second and participation
(SI) (SI) f piern and optineurin of The autophagy receptors and and receptors autophagy The . non 52
These results support the the support results These - sfr of isoform membrane vesicles, called called vesicles, membrane
kDa) and TAX1BP1 ( TAX1BP1 and kDa) - [51] - functional functional dependent clearance ofclearance dependent Tee idns are findings These . - idn st exactly site binding . MYO6 MYO6 MYO6
c isd an inside ect (Microtubule mitochondria hrough their their hrough [49]
recruitment
is MYO6
. - st
- positive positive - bind tethers tethers MYO6 known known r onger Tax1 [51]
ing ing ge th in - - - - .
This article isThis article by protected copyright. All rights reserved. the regulate to appears functionally and GluA2, and GluA1 subunits, receptor AMPA the tissues neuronal between MYO6 MYO of receptors. Gα the leukaemia myeloid acute in MLL with RhoA a is which ARHGEF12, as known with associated RhoGEF second The activity filamen actin enable to filaments actin from structures septin removalof theregulate might complex DISP filaments i and filaments actin from composition lipid and [63] curvature specific of membranes as well bindi as microtubules, and phospholipid with GTPases ring of or filamentous family large a are septins and LRCH3 I outgrowth myelinatio migration, cell Schwann in implicated been has and system nervous cytoskeleton actin the of regulators substrate toxin toward botulinum GEF DOCK a a as through act GTPases to appears Rho onto GTP of loading (DHR) region homology the catalyse which (GEFs), factors DOCK7 and and MYO6 protein and LRCH1 to actin. bind directly can which homologydomain, in involved (LRRs), repeats rich proteins assembly. and LRCH1 track actin th with highlights synchronised and is theme activity regulatory this on significantly builds MYO6 membrane plasma the at formation patch actin SPIRE2 nucleator actin the to binding by tracks actin of assembly with targeting motor coordinate to shown a of modulation dependent myosins IX but filaments, actin existing Accumulating MYO6 Accepted nduced Article . 6 Interestingly, overexpression of components of the DISP complex displaces the septins septins the displaces complex DISP the of components of overexpression Interestingly, -
adaptors functionsfor specialised adaptor regulat proteins soitd hGF opee, hc ln t dfeet ci mdltr pathways, modulatory actin different to link which complexes, RhoGEF associated 12/13 also appears to have a number of number a have to appears also
[18] S in a complex with complex a in MYO6 in membrane ruffles membrane in pi dis eptin
[60] DOCK7 ( DOCK7 G protein subunits and thus mediates RhoA activation downstream activation RhoA mediates thus and subunits protein G LRCH .
[57] (MYO9)
rognsto truh h DOCK7 the through reorganisation t evidence evidence
[61]
DC7 eog t te OK8 fml o gaie uloie exchange nucleotide guanine of family DOCK180 the to belongs DOCK7 . 3 of the LRCH ( LRCH the of 3 so far so , n SAP97 and
and myosins of class I can interact directly with proteins that regulate regulate that proteins with directly interact can I class of myosins and
P - (SEPT) D . like structures, which associate with distinct subsets of actin filaments actin of subsets distinct with associate which structures, like
aeet complex lacement) MYO6 ed ae hGP oan i ter tails their in domains RhoGAP have
[65] - icator icator indicates 2 domain and the and domain 2 , in particular SEPT7, but also SEPT8, SEPT9, and SEPT10. Septins Septins SEPT10. and SEPT9, SEPT8, also but SEPT7, particular in , . , LRCH3 and DOCK7 form a tripartite complex, the DISP ( DISP the complex, tripartite a form DOCK7 and LRCH3 ,
nduces the formation of cytosolic actin rings. Dynamic actin actin Dynamic rings. actin cytosolic of formation the nduces MYO6 I
1 also ndeed, ndeed, tn dynamics ctin ( ) O S
ynapse ynapse n CDC42 and for example are devoid of septin structures, therefore, the therefore, structures, septin of devoid are example for e f L
actively induce actin tracks as required. For example, class class example, For required. as tracks actin induce actively eucine C actin actin dynamics track that myosin motors do not simply translocate along pre along translocate simply not do motors myosin that s . These proteins comprise a series of N of series a comprise proteins These . yto
rnltd ebae oaie RAC1 localised membrane prenylated MYO6
K [59] [64] MYO6 inesis - a specific RhoGEF first identified as a fusion product product fusion a as identified first RhoGEF specific
R ssociated
[18] - ich repeats ich . Functionally, DOCK7 acts predominantly in the the in predominantly acts DOCK7 Functionally, . reby activat reby . rti itrcin, n a C a and interactions, protein
distinct tissue distinct has been identified in a complex with SAP97 and and SAP97 with complex a in identified been has
; LARG is among a family of RhoGEFs activated by activated RhoGEFs of family a among is LARG
(
BoD aa eeld osbe ik between links possible revealed data BioID . ls V myosins V class C 7 s AG ( LARG is ell ) thus constituting thus )
[54] d P ivision - rotein stimulated RAC1 and CDC42 GTPase GTPase CDC42 and RAC1 stimulated
C ing [55]
n situ In alponin L
-
eukemia them specific
[56] c g ciiy ht sebe into assemble that activity ng 97 ontrol protein protein ontrol wih euae RhoGTPase regulate which ,
) rxmt lblig identified labelling proximity
LRCH . The recent identifi recent The .
( H [58] MYO5 a ol be reported been only has omology
e extent to which motor motor which to extent e - functions. the linker between linker the a . In the case of DOCK7 it it DOCK7 of case the In . ssociated 3 associate directly3 associate )
have - terminal calponin calponin terminal domain) family of family domain) -
terminal leucine terminal 42 (
T Ra recently been been recently he interaction interaction he R ) n and neurite and n
ho , two major major two , s of - related
G a number a cation of cation F, also EF), D OCK7 MYO6
with with [62] C in 3 - - -
This article isThis article by protected copyright. All rights reserved. binding enhance or membrane mitochondrial outer the proteins [16] with directly interact domain ( Domain a sites, includes which optineurin [75] domain, Q9UM54 sequence MYO6 canonical to refer the motif, phospholipid The flexible tail domain. filaments actin to bound domain motor partners binding their of set data limited A MYO6 transcription co suggested been also has MYO6 Finally, microvilli inpolarised epithelial cells apical of intestine. maintenance for small required be may the MYO6 and in PLCδ3 of microvilli complex functional of a Thus, number the decreases enzyme the of loss and mouse decrea is however, MYO6, of expression The mouse. KO PLCδ3 the in observed were abnormalities hearing no cells, hair ear inner in expressed phosphoinos two yeast A [70] ear the in function cell hair normal in proteins these for role complementary a suggests this ganglia neurons to transmission signal and exocytosis for cells hair these of membrane basolateral otoferlin the at synapses ribbon The specialised the to vesicles neurotransmitter targeting in participate exocytosis. synaptic of sensor cells, hair ear inner In fashion activity an in surface cell the from or to receptors the of endocytosis or delivery
Accepted - Article ciao NP2 n h nces n t rglt RA oyeae II polymerase RNA regulate to and nucleus the in NDP52 activator
. cargo [71] [51] Point mutations in the RRL motif inhibit MYO inhibit motif RRL the in mutations Point
Molecular interactionsMolecular
1122 [66]
. M . . [68] h adaptor the This may involve direct binding of MYO6 to MYO6 binding of direct involve may This
- MyU n addition In
otif otif binding adaptor - [16] 1131
- [67] hybrid screen has identified phospholipase C (PLCδ3), an important enzyme in enzyme important an (PLCδ3), C phospholipase identified has screen hybrid partner binding MYO6 a as metabolism, itide
[73] [69] binding
b
I
trcig with nteracting the [77] (PIP2) )
[65] 998 to MYO6 adaptor proteins that proteins adaptor MYO6 to
. [74]
tail domain tail Since mutations in both in mutations Since - binding binding
WWY motif WWY 1 [78] 025 . , structural information is available on the tail domain tail the on available is information structural
domain . adaptor proteins such as GIPC as such proteins adaptor
binding MYO6
[20] h MU my a may MyUb the
[20] which , .
Dab2, LMTK and LMTK Dab2,
[21] domain 1 domain 7, 79] [78,
binds to otoferlin, a transmembrane protein and putative Ca putative and protein transmembrane a otoferlin, to binds
(see f (see contains oan 2 domain
[75] U [15] vras ih the with overlaps iutn (MIU) biquitin igure . [72]
[29] To date, cryo date, To (ABD1) [21] indirect binding via free ubiquitin chains ubiquitin free via binding indirect protein to function together with the putative transcription putative the with together function to .
lw niet binding indirect llow [76]
(ABD2) 1 D and figure and D 1 T . [30] TOM1 MYO6 , the on used be to yet has technique this but , ruh t hrough
. The tail also contains two ubiquitin two contains also tail The . encompasses - - uniprot) 3 binding
contain a ubiquitin binding domain binding ubiquitin a contain 99 -
otis the contains MYO6 proteins
0 - and otoferlin cause deafness in humans in deafness cause otoferlin and - 6 EM has been successfully applied to the the to applied successfully been has EM 10 ,
, TAX1BP1, NDP52 and optineurin and NDP52 TAX1BP1, ,
1 binding to binding for example for 4 ABD1 sed in the intestine of the PLCδ3 KO PLCδ3 the of intestine the in sed he
motifs n a and
2 complex has been suggested to to suggested been has complex ) ABD all all and . 1084
The the
interact interact [72] , ubiquitin , via 1/ - WWY My 1128 h scn protein second the GIPC, RRL yb domain MyUb first MYO6 protein MYO6 first ,
. sn VI osin ubiquitin ubiquiti
Although PLCδ3 is also also is PLCδ3 Although 11 and 1 201 16 NDP52, TAX1BP1 and and TAX1BP1 NDP52, with MYO6 with - - 11
1 - binding 203 18 the n U
ated proteins on on proteins ated
motif with biquitin chains motif
lipid binding binding lipid , which may may which , - -
MYO6 dependent dependent dependent sites or without without or
(positions (positions via via [20] to ,
- - -
B binding binding binding binding such as such
inding ABD and other
[21] [52] can can 2,
2+ a ,
This article isThis article by protected copyright. All rights reserved. bind Acceptedoptineurin and TAX1BP1 (RL leucine and arginine second four these of binding binding Interestingly, the GIPC of binding Direct functions which without MYO6 dimerised artificially tips an the Interestingly, at MYO6+ with together accumulates which only GIPC, of formation presence filopodia the in induced occurs MYO6+ filaments. actin of end plus the towards moves of importance the of formation the interactions hydrophobic allow with interacts second the of middle the C its via GIPC dimer the to directly binds GIPC MYO6 roles andfunctions oligomerization even Articlehowever transporter. or anchor an as state oligomerization its on effect the and adaptors cargo domain tail α of presence increased an to leads lipids to MYO6 of binding as organisation, simultaneously which ABD for hindrance the to amphipathic prior located is isoform extra PC in cortex actin the to granules secretory of tethering regulates which providing by mechanisms i motif regulatory t example, For sites. additional binding protein adaptor allow or motifs phosphorylation regulatory MYO6 of variants to splice proteins adaptor of binding regulate might site this at MYO6 inhibited EINE to sites phosphorylation optineurin TAX1BP1, TOM1, opposite 1
- R motif RRL indirectly via ubiquitin chains ubiquitin via indirectly MYO6 complex can assemble into assemble can complex MYO6
, whic ,
[28] may increase flexibility for cargo for flexibility increase may s a potential c potential a s ABD1 support . Furthermore . - , terminal GIPC terminal
in vivoin the interaction with interaction the .
h opens up upon cargo binding to binding cargo upon up opens h Betwee [78]
and MyUb and MyUb domain
α side of the of side five, or even longer, even or five, this region is dispensable for ubiquitin binding, but essential for essential but binding, ubiquitin for dispensable is region this binding of the of binding - s h to riie ( arginines two the . helix that contains a clathrin a contains that helix
. . h iprac of importance the
u as te egbuig extended neighbouring the also but
utemr, rti bnig tef a idc uiu structural unique induce may itself binding protein Furthermore, In the next section, we will focus o focus will we section, next the In
the
MYO6 n of MYO6
- ,
the (see figure 1 figure (see
src
TINT direct binding partners binding direct the presence of the extra α extra the of presence the , binding of MYO6 to optineurin, suggesting that phosphorylation of of phosphorylation that suggesting optineurin, to MYO6 of binding -
homology 2 (GH2) domain to t to domain (GH2) 2 homology but also the other adaptor proteins adaptor other the also but MYO6 - not only only not
kinase phosphorylation site only present in the in present only site phosphorylation kinase
ABD α lgmrzto nue y GIPC by induced oligomerization 10 - ABD helix in MYO6 in helix
96
as as Upon purification MYO6 appears MYO6 purification Upon adaptor - 1 1
different cargo different
C 100 a [20] 1
and 11 and BD encompassing theencompassing motif RRL
monomer ordimer. monomer
17 linear GIPC linear [78] interact interact B and DYD and RR
ABD ) ,11 . The . covering the covering
to GIPC
[75] ABD 11 proteins GIPC, NDP52, TAX1BP1 and optineurin to the the to optineurin and TAX1BP1 NDP52, GIPC, proteins 18 NDP52 In .
the 16 ) of the RRL motif RRL the of ) 1/ -
binding , linear linear -
11 2 GH2 domain of the of domain GH2
[19] eitd dimerization/oligomerisation mediated yB domain MyUB
t iatv form inactive its
directly 17 ABD2 MYO6 11 n h ti tee s a is there tail the in - )
binding site binding 45 -
MYO6 oligomers MYO6
- of the RRL motif and an extended region to to region extended an and motif RRL the of interact with interact [20] [53] - adaptor proteins adaptor to MYO6, as it excludes their binding to binding their excludes it as MYO6, to 11 higher
10 to 47 leucine ( leucine
- MyUb domain MyUb 84 , .
helix introduced by the LI isoform inhibits isoform LI the by introduced helix
with
allow different adaptor proteins to bind bind to proteins adaptor different allow and thus determine thus and
- [21] 1 Phosphomimetic mutations of the TINT the of mutations Phosphomimetic n the interaction of MYO6 with various with MYO6 of interaction the n 128
- order oligomers order the CBD, CBD, the he RRL motif RRL he . MYO6
.
The
[28] L yrpoi surface hydrophobic which is important for i for important is which n frs uiu regulatory unique a forms and 11 [28] T
the RRL motif RRL the
he 18 GIPC
through second GIPC second GH2 of the first the of GH2 . This helix also provides steric steric provides also helix This . to the ABD1 the to
)
. . [52] to be to of the RRL motif RRL the of
In vivo In In MYO6 may induce dimerization or dimerization induce may can
[21] ag usrcue region unstructured large xss as exists contrast
ABD [51]
, which , a monomer a rescue
uat MYO6+ mutant a [22]
, observations support observations 1 , in which in
the detailed cellular detailed the CBD -
but 12 cells 12 [16]
in . molecule molecule MYO6 not only not
n autoinhibited an
to GIPC to hs phenotype this
is embedded embedded is MYO6 interact MYO6 MYO6 potentially . GIPC direct adaptor direct contains two two contains - The different different The helices in the in helices 11
allowing the allowing
2 [49] in vitro in GIPC SI 3 ts function ts for -
11 molecule molecule
[20] , isoform, isoform,
requires binds to to binds 31 he DYD he NDP52, NDP52, . MYO6
The
binds
.
[36] [21] that that
also The The [8] the the re
in in LI LI s - . . , , ,
This article isThis article by protected copyright. All rights reserved. MYO6 the whether distinguish interaction ubiquitin requires to chains oroccur required, is analysis biochemical and structural ubiquitin the using the via directly occurs MYO6 and motif, WWY TOM1 between TOLLIP interaction partner the its although and that TOM1, of suggest loss the to leads also motif RRL the In simultaneously bind can NDP52 and that shown have proteins purified using experiments motif WWY LC the mammalian 2 the to binds also TOM1 clathrin with associated proteins other and Dab2 endocytosis upon mutationof WWYsite the of loss the demonstrated [75] clathrin to localization cellular abolish throu motif, binding either Dab2 of MYO6, with and interacts affinity Dab2 binding the increasing thereby II interactions between interactions site hydrophobic binding allowing whereas site, binding major the is I Site dimer. the stabilising thereby orientation reverse the in Dab2 second a by occupied motif IWE the and monomer MYO6 one on motif WWY the to binding by MYO6 of dimerization induce WWY the tw contains CBD MYO6 The α2 the in identified been has that region binding (PIP motifs Dab2 involves membrane plasma MYO6 of dimerization induce to suggested been has example, for Dab2 adaptor clathrin the with MYO6 of interaction The MYO6 support K11 in however, linkages; ubiquitin Parkin by degradation for marked mitochondria ubiquitinated with interacts directly and recognizes motif binding MIU the or MyUb the via proteins ubiquitinated with interact directly also can MYO6 Finally, chains. m receptors MYO6autophagy the with MYO6 of interaction a forming thus simultaneous, three K11 and K29 K63, K48, with
Acceptedsitu in terestingly, Article 2
) [52]
-
[75] 3 [21]
adaptor interactionmotifthe WWYbinding at ihn the within
- binding autophagy receptors (NDP52, TAX1BP1 and optineurin) and through the the through and optineurin) and TAX1BP1 (NDP52, receptors autophagy binding Te motne f ie ws ofre by confirmed was I site of importance The .
motif) and site II (including the IWE the (including II site and motif)
of another of . n vivo in [80] - in vivo in oh Y6 n TXB1 ae en hw t bn t K3 Ub K63 to bind to shown been have TAX1BP1 and MYO6 Both linked ubiquitinbind - hybrid in vitro in hybrid in n h asne of absence the in
[81]
ABD ABD [22]
- the binding between MYO6 and MYO6 between binding the
idn TM VS oan n te Y6 yb oan A detailed A domain. MyUb MYO6 the and domain VHS TOM1 binding proximity labelling of MYO6 NI CBD has indicated that the mutation of of mutation the that indicated has CBD NI MYO6 of labelling proximity [52] [75] 2 . 2
ad idn t PtdIns(4,5)P to binding and , W h MU idn mtf hw n afnt o peeec towards preference or affinity no shows motif binding MIU The I adto, MYO6 addition, In . ih TOM1 with . The remaining two binding sit binding two remaining The .
1 W motif WWY 202 o discrete spatially separated Dab2 binding sites, site I (including (including I site sites, binding Dab2 separated spatially discrete o
[30] linked ubiquitin chains, with a clear pref clear a with chains, ubiquitin linked
of WWY or W or WWY of [75] cooperation . MYO6 may simultaneously interact, throughinteract, its simultaneously may . MYO6 ing. - n o te nw cargo known the of any binding via the WWY the via binding . Targeting of MYO6 to clathrin to MYO6 of Targeting . -
positive endocytic vesicles vesicles endocytic positive -
directly - otd tutrs t h pam membrane plasma the at structures coated ubiquitin n the in
[18] 12 with the MyUb domain it seems to specifically to seems it domain MyUb the with s
motif). Structural data suggests that Dab2 may Dab2 that suggests data Structural motif).
may 62 b y direct binding.y direct
o the to ABD . of IWE, disrupt Dab2 binding to MYO6 and and MYO6 to binding Dab2 disrupt IWE, of
- A1P complex TAX1BP1 -
linker helix of the LI splice isoform splice LI the of helix linker interact directly with clathrin through a a through clathrin with directly interact [75] TOM1 may also be indirect via ubiquitin ubiquitin via indirect be also may TOM1 2 2 ,
ay have extra regulation via ubiquitin via regulation extra have ay
two adaptor proteins such as TOM1 as such proteins adaptor two i te phospholipid the via as determined by pull downs and and downs pull by determined as hydrophobic and charge both gh . Point mutations of the tryptophan tryptophan the of mutations Point .
MYO6
es on the two MYO6 monomers are monomers MYO6 two the on es and n situ in - dpo proteins. adaptor IWE
ABD
12 rxmt lblig which labelling, proximity - 61 coated structures at the the at structures coated ad the and 1 [82] - 1 2 [22] 63 erence for the latter the for erence
Indeed, . [18] protein Teeoe the Therefore, . Tee results These . domain
MYO6 MyUb MyUb MYO6 ABD - interaction ABD - mediated 4 2 n vitro in
11
- n vivo in chains chains 1 TOM1 22
[28] [52] with with - 11 31 . .
This article isThis article by protected copyright. All rights reserved. filamentactin populationscontaining distinct tropomyosin isoforms. filaments containin filaments filaments. actin distinct functionally to myosins specialised of recruitment select the to leads and motors myosin of assemblies iso tropomyosin these of presence filament actin distinct temporally and spatially decorate which non In muscle. striated troponin with together the tropomyosin, hasbeenwell respect oneis which mostimportant probably a of number large a by regulated also is but filament, a up make β non isoforms actin different by activated differentially is MYO6 whether known not is non N their in residues tissues and types cell most ( isoforms actin cytoplasmic two The cells. muscle in present in expressed isoforms actin different six the From domain of non F of states nucleotide filaments ADP+Pi on lengths run increased a rigid less is filament the of end minus the ADP and actin ATP sequential flow retrograde and ATP new of addition constant the Throughmembranes. internal plus ATP the new to of monomers addition the actin by assemble that structures dynamic highly are filaments Actin the and present proteins binding actin the involved, nucleotide isoform actin the to responsive is activity myosin as regulation of layer first the provides composition track filament actin The ATP of Actin trackcomposition activation with binding cargo of timing the coordinate hydro to family myosin the some myosins, most in present are regulation net actin non random control further To filaments. ATPases, motors myosin All Potential mechanism - Accepted ATPase whereas actin activityofMYO7A Article - - muscle muscle myosins of classes different with associate preferentially and cells muscle lysis and force production.lysis andforce A ctivation of select myosin motors is not only influenced by the actin isoforms that that isoforms actin the by influenced only not is motors myosin select of ctivation
work, tight regulation of myosin mobilisation is required. Several layers of of layers Several required. is mobilisation myosin of regulation tight work, n this and [89] [6] - state o myosin IIc (MYH14) IIc myosin Rcn cryo Recent .
- [90] - Pi actin filaments have very similar properties, the ADP the properties, similar very have filaments actin Pi muscle myosinclass muscle
f the actin monomer. f theactinmonomer. . rvns uie T hdoyi we temtr s o atce t actin to attached not is motor the when hydrolysis ATP futile prevents
g - , Future studies will show whether MYO6 preferentially binds to different different to binds preferentially MYO6 whether show will studies Future
emnl sequen terminal Tm2 ih h ecpin of exception the with s -
actin actin for regulationactivity ofMYO6motor -
o is oe n Ca in role its for uce el 40 cells muscle , whereas MYO5A selectively engages with Tm3.1 with engages selectively MYO5A whereas , o example, For - M tutrs ofr mnr ofrainl hne between changes conformational minor confirm structures EM [84] A . - n o flmns t h pam mmrn o te ufc of surface the or membrane plasma the at filaments of end tog tee w ctpamc cis ny ifr by differ only actins cytoplasmic two these lthough , as well as within the actin binding interface of the motor motor the of interface binding actin the within as well as , shows -
rich filaments, whereas MYO6 which prefers ‘old’ ADP ‘old’ prefers which MYO6 whereas filaments, rich forms on different actin structures modulates the affinity the modulates structures actin different on forms
- IIc (MYH14) and IIc (MYH14) hydrolysis, referred to as referredageing.filamentATP hydrolysis, Whereas ce
, increased kinetics when interacting with cytoplasmic cytoplasmic with interacting when kinetics increased
hy a asml it dsic atn tutrs in structures actin distinct into assemble can they ysn ls I ( Ic class myosin tropomyosin 2+ - productive translocation along the dense cellular dense the along translocation productive results in greater stimulation in greater by results
regulation of of regulation ls XII ( XVIII class nd stable. Interestingly, Interestingly, stable. nd being
mammalian cells, four isoforms are only are isoforms four cells, mammalian
unique MYO6.
(Tm)
MYO18 MYO1C sarcomeric sarcomeric [85]
and other being other and isoforms
- cyto and cyto
- ctin binding proteins. In this this In proteins. binding ctin [76] a ) ctin the filaments undergo undergo filaments the ctin )
[83] os not does
.
-
ae en identified, been have myosins n vitro in actin accumulating at at accumulating actin ,
r actin are - cyto) are found in in found are cyto)
– γ
universal across across universal decorated actin actin decorated -
actin actin [87] -
id to bind . characterised MYO5 shows shows MYO5 f ls II class of At present it present At ,
- however, [88] [86] activated The . . actin - four
rich rich
in in - -
This article isThis article by protected copyright. All rights reserved. many in linchpin the is MYO6 that cellular functions. highlighting further discovered, be will interactions in that rece With pathways. motor cellular different to linked networks protein of number a in a it make MYO6 of be easily cannot characteristics biochemical and mechanical unique The Conclusion and Perspectives high of is this presence own its on the however, state, probably notaneffective method ofregulationwithin the cell. active in and inactive unfold the between equilibriums also shifting MYO5 can to similar partners molecule binding of concentrations backfolded The translocation. Ca low facilita now can arm lever the restored the bound is cargo to if conformation, backfolded return a in and cargo, cargo bind to able readily more it making position “primed” a into e domain tail the simultaneously cargo, translocate cannot molecule the so arm, lever 3 the de lobe Ca of number the on depending conformation change The molecule. the into ‘locked’ is that calmodulin two has MYO6 to, and domain. boundchanging neck the conformationofcalmodulin to 50 reduced back tail the where X) and VII VI, V, (II, family myosin the in theme recurring a is hydrolysis ATP inactivate to way a as Backfolding Backfoldin its by Thr405 PAK accompanied through MYO6 activate is to suggested been and have SopE, activation receptor ruffles membrane factor to recruitment growth of downstream domain occurs motor myosin for Ser) event or Asp Glu, Thr, Thr405 a be either and Bement by must postulated phosphorylation (it rule TEDS the motor the in threonine or sta inactive folded c) and b Ia, (myosin a from myosin the state active unfolded of changes structural non dramatic example, trigger For the mechanism. of phosphorylation by regulatory regulated important another are filament actin the with crosstalk through post activity track, motor of regulation the to addition In Regulationof MYO6
Acceptedproteomics functional Article -
helix bundle helix affects
taches from the heavy chain and rebinds to a higher affinity binding site present in present site binding affinity higher a to rebinds and chain heavy the from taches [94] n h crimoah lo i te ci bnig region binding actin the in loop cardiomyopathy the in g regulates kinetics g ATPase - - translational modifications of the myosin heavy chain or associated light chains chains light associated or chain heavy myosin the of modifications translational . fold
the K the
calmodulins bound at the neck domain. The The domain. neck the at bound calmodulins [98] replaced
-
ATPASE
folds onto the motor domain, in this confo this in domain, motor the onto folds [95] at the beginning of the tail the of beginning the at have been shown to be regulated by regulated be to shown been have
. In the case of MYO5 this backfolding is regulated by calcium binding binding calcium by regulated is backfolding this MYO5 of case the In . through phosphorylation [91]
[96]
but not the V the not but
we believe that an even greater number of transient, short transient, of number greater even an that believe we . in the cell. cell. the in which In
[97] Acanthamo . MYO5 has been shown to take a compact conformation, compact a take to shown been has MYO5 . enhances the actin activated ATPase activated actin the enhances [44] MYO6 regulatory
. max max 2+ Moreover, eba
[9] odto te oeue il eae compact a retake will molecule the condition
bind Mooseker , . Phosphorylation in the MYO6 motor domain domain motor MYO6 the in Phosphorylation .
several of the myosin class I family members family I class myosin the of several s [97] light chains by a variety of kinases, which kinases, of variety a by chains light
a large range of cargoes of range large a
amnla iuec effectors virulence Salmonella second . This has the effect of “breaking” the “breaking” of effect the has This . [99]
2+ [93]
ions bound. Upon binding Upon bound. ions
phosphorylation ti my simply may this , .
MYO6 is is MYO6 calmodulin has been shown to to shown been has calmodulin - dependent phosphorylation at phosphorylation dependent first
rmation the ATPase activity is activity ATPase the rmation ,
calmodulin is a is calmodulin and this phosphorylation phosphorylation this and [97] also - uce MYO2s muscle [92] . In the absence of absence the In . phosphorylated at at phosphorylated
and at a single serine single a at .
e mte of matter a be This site obeys site This
act nt advances nt s structural , te to an an to te
te active te
Ca as a hub hub a as such as as such 2+ - nters
lived lived one one are are
This article isThis article by protected copyright. All rights reserved. R. Y.Biritwum, D.Tettey, E. C.Yeboah, S.Pettaway, S.Holt, S. H. E.Strom, A. K.Rinckleb, L.Kolb, M.Herkommer, J. A. J.Stanford, D. B.Coll, K.Schaid, S. S.Knudsen, N.McDonnell, S. P.Thibodeau, A.Iversen, M. P.Roder, F.Klarskov, S. G.Nielsen, B. M.Nordestgaard, N.Weischer, P.Pashayan, T. M.Pharoah, C.Key, R. K.Guy, J.Travis, M.Govindasami, M.Donovan, J.Aly, A.Xu, C.Ahmed, K. T.Leinonen, J.Visakorpi, K.Goh, T.Schleutker, A.Wahlfors, L.Auvinen, A.Yu, T. M.Tammela, C.Hutchinson, C. L. L.Chung, X.Pooler, M.Burdette, A.Sheng, N.Le P.Stram, L. J.Kolonel, K.Wan, L.Tyrer, K.Xia, O.Rand, S.Jugurnauth C.Park, D. D.Lindstrom, M.Stram, E.Leongamornlert, T.Tymrakiewicz, Z.Saunders, S.Dadaev, J.Wang, D. VI myosin S.Hazelett, A.Kote of A. mechanism Olama, The Al (2004) A. 11. J. Spudich, & L. H. translocation anditsload Sweeney, D., Altman, 10. of myosin VI, mechani Kinetic (2001) L. H. Sweeney, & M. E. Ostap, M., E. Cruz, La De 9. myosinVI A monomeric withalarge working stroke, Kendrick & C. Veigel, F., Buss, J., Trinick, M., Walker, S., Schmitz, I., Lister, 8. (2001) L. H. Sweeney, & A. J. Spudich, J., Myosin VIaprocessivelargestep motorwitha issize, T. Purcell, L., A. Wells, E., S. Rice, S., R. Rock, 7. orch age Actin (2015) S. R. Rock, & myosin R. D. of Kovar, A., mechanism Santos, the D., Zimmermann, reveals 6. motor VI myosin the of directionality reversal, structure The (2005) A. L. A. Houdusse, Wells, A., Bahloul, J., Menetrey, actin 5. an is VI Myosin (1999) L. backwards, H. O., B. Sweeney, Carragher, T., & Hasson, M., A. S. Cain, R. D., Safer, Milligan, Q., L. Chen, the W., A. on Lin, L., based A. Wells, life 4. eukaryotic of tree the Drawing (2007) M.ofanalysis annotatedmyosins 2,269 from328 manually species, Kollmar, & F. Odronitz, 3. classification, and evolution myosin into insights New (2006) D. Soldati, & C. M. Goedecke, J., B. Foth, 2. 12 census, myosin millennial A (2001) E. R. Cheney, & C. B. Powell, S., J. Berg, 1. References funds.studentship to theCIMRdepartmental J. J. de from Council Research Medical the limitation. We Acknowledgements improve humanhealth. the A understood. mechanism the been has progress some Although
Accepted Article, 780
plgs t or olaus hs wr w wr ual to unable were we work whose colleagues our to apologise ag bnig domain binding cargo aucit Ti wr ws udd y rns rm h BSC (BB/ BBSRC the from grants by funded was work This manuscript. - - 5 and myosin 5 and 94.
We thank Dr Jo Dr thank We
Nature. Nature. J Biol Chem.J Biol Proc NatlAcadSci U A. S nswering these questions these nswering s
which constrict the selection, substitution and release of cargo of release and substitution selection, the constrict which 401
- 6 run lengths, 6 run Nature. , 505
- 276 induced anchoring, induced h - asu, . .ie, . .tvn, . .ae, C.Luedeke, L.Maier, V. R.Stevens, W. M.Diver, S. Gapstur, , aa, .ent S I.C S. Z.Berndt, Jarai, n Kendrick n
- r cuil for crucial are 8. (MR/ , 32373 435
N000048 , 779, made Curr Biol. Curr J.Siddiq, A.Canzian, F.Khaw, K. T.Takahashi, A.Kubo, A.Kubo, T.Takahashi, K. F.Khaw, A.Canzian, J.Siddiq, - 81. - Jones 103 -
85. as well as further structural details, in particular of of particular in details, structural further as well as
with the with acad LHoe, . .ahea M J.Yeager, M. N.Machiela, R. L.Hoover, Marchand, , 3681 , Yengo, C. M., Morris, C. A., Sweeney, H. L. & & L. H. Sweeney, A., C. Morris, M., C. Yengo, ,
/1
sn MO a a uue hrpui tre to target therapeutic future a as MYO6 using and Dr Antonina J. Kruppa J. Antonina Dr and Cell.
25 n MR/S007776/1 and , 2057 - ni D VShmce, .a, Y.Benlloch, F.Han, V.Schumacher, D. onti, 6.
understanding of the regulation of MYO6, MYO6, of regulation the of understanding 116
EMBO J. EMBO Proc NatlAcadSci U S A. , 737 - 62.
- 49.
23
, 1729 Genome Biol. - based motor that moves moves that motor based t FB ad PhD a and F.B. to ) - 38.
c for critical reading of reading critical for ite
sm and regulation and sm R001316/1 wn t space to owing - Jones, J. (2004) J. Jones, 8 98 Mol Biol Cell. Biol Mol , R196. are , 136 ,
estrates estrates still not still - 55
) and and ) Little, Little, - 9.
This article isThis article by protected copyright. All rights reserved. AcceptedVI, PTH (2009) M. Levi, & N. Barry, A., Millard, Y., Caldas, S., Breusegem, H., Giral, K., Okamura, J., Blaine, 26. channelschloride intheintest VI myosin Alpha (2010) N. Ameen, & M. Mooseker, P., Hegan, R., Jakab, A., Collaco, 25. Cytoskeleton (Hoboken). lacking mice in histology and endocytosis tubular proximal renal Altered (2010) T. Wang, & S. M. Mooseker, M., Kashgarian, D., Biemesderfer, Z., Du, Q., Yan, N., Gotoh, 24. endocytos apical VI CFTR Defective Myosin (2007) brush borderinmyosinVI G. (2018) Apodaca, & F. N. Ameen, Buss, 23. & M. Minczuk, Encapsulate Parkin A., the J. Nathan, of J., mechanism Kishi J., A. Kruppa, 22. Compact oligomerization a Contains VI Myosin MotifStructural Chains, that Bindsto Ubiquitin (2016) J. K. Biancos Walters, & U., S. regulated Polo, Nowicka, E., Magistrati, P., F., Acconcia, H. Wollscheid, a F., He, 21. reveal PlexinD1/GIPC/myosin VI complex, analyses Torres D., Lu, R., Chen, Structure A., C. Brautigam, G., Shang, 20. bindingCargo inducesdimerization of myosin VI, (2009) L. H. Sweeney, & D. Safer, B., A. Zong, X., Liu, Z., Yang, M., Travaglia, D., Phichith, 19. complexes coordinatingearly endosome c and adaptor reveals interactome MYO6 The (2018) F. Buss, & A. T. Masters, T., O'Loughlin, 18. Proc NatlAcadSci U SA. the study to approach Proteomics (2011) A. J. o functions Spudich, & A. M. Hartman, D., Finan, 17. Article P., J. Luzio, involvedGolgi inandexocytosis, organization J., M. Taylor, G., Spudich, D., S. Arden, Kendrick C., R. Roberts, A., D. Sahlender, 16. mediated cytoskeleton,endocytosis theactin and Buss, Kendrick C., R. Roberts, D., S. Arden, M., S. Morris, 15. dissemination ofhuman ovariancancer, fro Lessons (2004) H. Naora, & J. Liu, D., Rosen, E., Geisbrecht, D., Montell, J., Hung, W., Cheng, H., Yoshida, 14. modeldisparate organisms, M., Na C. 13. Ewing, Y., Chen, in VI A., myosin of E. role novel Platz, A human prostatecancer, (2006) L., J. Luo, J. & M. Hicks, A. Marzo, A., De B., D. W. Isaacs, Faith, J., Sauvageot, S., Chen, A., T. Dunn, 12. 1103 cancer, prostate for loci susceptibility new 23 identifies individuals 87,040 meta A (2014) al. et L., E. C.Giovannucci, C.Chen, K.Stegmaier, A. H.Dieffenbach, P.Cannon A. D.Kl S.Chokkalingam, C.Wokolorczyk, A.Niwa, E.Truelove, A.Tay, A. B.Adjei, Am J Physiol Cell Physiol. Am JPhysiol -
9. . 20) ysn I id t ad oaie wt Db, oetal lnig receptor linking potentially Dab2, with localises and to binds VI Myosin (2002) F. ora, H. & Montell, D. J. (2005) Ovarian cancer metastasis: integrating insights from insights integrating metastasis: cancer Ovarian (2005) J. D. Montell, & H. ora,
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This article isThis article by protected copyright. All rights reserved. (SI) mitophagy. during drive MYO interact MYO6 C. MYO6. monomers MYO6 two bind can dimer optineurin one TOM1 with tethering and ( partners. domain binding binding cargo its with denoting structure, interaction and structure MYO6 1: Figure docking partnerofa specific Va, myosin melanophilin, by function Va myosin of Activation (2005) M. Ikebe, & R. Ikebe, D., X. Li, 99. atthecalcium single by processivity V myosin of Regulation (2006) M. K. Trybus, & B. E. Krementsova, H., Lu, 98. and activate myosin Br C., Batters, 97. Proc NatlAcadSci U SA. head the to binds tail M. The Ikebe, & (2009) R. Craig, R., Ikebe, D., X. Li, T., Sakai, S., Watanabe, S., H. Jung, N., Umeki, 96. The cargo (2006) J. P. Knight, & R. J. Sellers, 3rd, A., J. Hammer, & T., Sakamoto, K., Thirumurugan, F. 95. Buss, D., S. Arden, C., signaling an A. Davidson, V., Singh, D., SalmonellaPI3virulenceby trigger effectorsto targeted is (2017)MYO6Koronakis,V. Humphreys, B., for A. rationale Brooks, molecular 94. a rule: TEDS (1995) Cytoskeleton. S. M. phosphorylation by Mooseker, myosins of & regulation differential M. W. Bement, 93. phosphorylation, & H. Brzeska, 92. 436 non vertebrate of conformation Kendrick & R. Smith, R., Craig, 91. isoforms actintrack by bias selection vertebrate myosin Va, Tropomyosin (2016) M. K. Trybus, & M. D. Warshaw, B., E. Krementsova, M., Sckolnick, 90. and initiation the of Biol. Control (2015) M. E. Ostap, & L. te E. Holzbaur, Actin B., (2019) B. W. McIntosh, P. 89. Gunning, & C. E. Hardeman, M., C. distributioninnon tropomyosin Specify J. Meiring, Isoforms J., D. Tropomyosin Manstein, (2017) 88. P. Lappalainen, & A. Functionally DistinctActin Vitro, PopulationsFilament In Michelot, W., J., P. Gunning, D. L., Gressin, K., Manstein, Kogan, T., Kotila, T., Reindl, E., Kremneva, G., Gateva, and 87. isoforms actin between interactions functional Distinct myosins, nonsarcomeric (2013) J. D. Manstein, & H. M Taft, M., Preller, M., S. Heissler, P., Claus, I., Chizhov, P., R. Diensthuber, M., Muller, 86.
Accepted Article kinesin of rmination
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may interact with interact may may interact simultaneously with simultaneously interact may , 523 large - binding domain regulates and structure ofactivity myosin5, d pathogeninvasion intohostcells, -
9. insert 31
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Korn, E. D. (1996) Regulation of class I and class II myosins by heavy chain chain heavy by myosins II class and I class of Regulation (1996) D. E. Korn,
ack, D., Ellrich, H., Averbeck, B. & Veigel, C. (2016) Calcium can mobilize mobilize can Calcium (2016) C. Veigel, & B. Averbeck, H., Ellrich, D., ack, D. MYO6 amino acid sequences based on the human the on based sequences acid amino MYO6 D.
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isoform PLoS One. - 106 one s rvn rnpr b myosin by transport driven
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idns ates n oioeiain states. oligomerization and partners bindings MYO6 monomer; two Dab2 monomers may dimerize MYO6 dimerize may monomers Dab2 two monomer; MYO6 271 - Poen idn dmis and domains binding Protein . - muscle cells, muscle muscle and smooth muscle myosin molecules, myosin muscle smooth and muscle , 16983, - - - ; MYO6 interacts with ubiquitin (UB) (UB) ubiquitin with interacts MYO6 ; 8 neck domain, inhibiting ATPase activity of myosin VIIA, VIIA, myosin of activity ATPase inhibiting domain, neck Jones, J. (1983) Light (1983) J. Jones, 8. , e70636., J Biol Chem.J Biol
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This article isThis article by protected copyright. All rights reserved. Accepted Articleorganisation via signalling. GPCR positive clathrin MYO6 line). dotted (green (green) motif WWY its via Dab2 chains. ubiquitin mitophagy ( domain MyUb d RRL its through optineurin and partners. MYO6 which in processes 2: Figure [75] (orange GIPC respectively sheets sequences sequence the above annotated
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This article isThis article by protected copyright. All rights reserved. Accepted Article
This article isThis article by protected copyright. All rights reserved. Accepted Article