Journal of Cell Science Aswt nepai nterrlsi euaigteactin the regulating in roles their on of functions emphasis 2009). cytoskeleton. biological eukaryotes an cell regulator. with and al., among actin CAPs biochemical important covers CAPs fundamentally et article a This is of CAP (Quintero-Monzon that conservation suggests activities the Furthermore, CAP its of self-oligomerization and enhances 2002), Yahara, and (Moriyama ci iaetdnmc oeta monomer- a than factor more sequestration – regulating dynamics in filament protein actin cyclase-associated of role The Commentary fCP tpooe ci iaetdnmc Bx1,closely 2) 1), (Box (Box dynamics ADF/cofilin filament Field, with actin and functions promotes cooperates Freeman biochemical It 2004; new CAP. revealed al., of have et studies function Bertling Recent 2003; 2000). actin-monomer-sequestering al., its et (Balcer by be cannot explained that reorganization biological has simply actin CAP dynamic cell that the suggested and in have roles genetic organisms important several hand, in CAP other of the studies On polymerization 2002). actin- from Mottillo, an and actin-binding as them monomers described actin additional prevent been sequester can has of that CAP protein hand, number monomer-binding of one patterns the a actin-cytoskeletal different On involve proteins. exhibit the cell that of However, types dynamics 2009). filament different 2010; in in Carlier, or Cooper, and actin structures cells (Bugyi motile and pathogens persistent of bacterial Pollard edge of actin-regulatory can of leading tails the comet capping of mechanism the at example, and set basic for The turnover, depolymerization minimal the cells. nucleation, a explain within controlled for of structures temporally proteins cytoskeletal functions and actin combined spatially of of enables disassembly dynamics and filaments assembly the actin of regulation coordinated The Introduction actin of regulator important an as implications Commentary its This and assembly. CAP in sarcomere of activities. words: filaments muscle functions cellular Key actin various the and in of of migration has involved severing understanding CAP cell are CAP. the our trafficking, which of in promotes dynamics, vesicle localization advances cytoskeletal also and development, recent activities and signaling, regulate the ADF/cofilin, proteins cell enhances discusses to other CAP in dynamics. to antagonistically filament roles binding CAP actin ATP and that crucial in shown with Self-oligomerization CAP have ADF/cofilin. of actin-regulatory monomers studies roles with Early of actin active cooperation years. variety more 20 of revealed A over have recharging for events. Cyclase-associated however, studied the biological reorganization. been studies, has cytoskeletal recent cell that monomers; actin of protein actin to actin-monomer-binding number sequesters contribute conserved a and a actin to is of (CAP) fundamental protein depolymerization is and cytoskeleton polymerization modulate actin proteins the of reorganization Dynamic Summary 10.1242/jcs.128231 doi: 3249–3258 USA 126, ß Science 30322, Cell GA of Atlanta, Journal University, Emory Biology, Cell of Department [email protected] and Pathology of Department Ono Shoichiro 03 ulse yTeCmayo ilgssLtd Biologists of Company The by Published 2013. ci unvr D/oii,Ccaeascae rti,Ncetd xhne Severing exchange, Nucleotide protein, Cyclase-associated ADF/cofilin, turnover, Actin nvitro in nvitro in Hbese and (Hubberstey and nvivo in euneadsrcueo CAP of structure and Sequence hra 2i escnevd–wt nol ctee appearance from of scattered CAPs only stretch an in with – a conserved conserved less highly with is is P2 – whereas P1 species 1A). (Fig. different P2) actin and ADF/cofilin-bound (P1 with 2). interacts (Box 2013) al., also et (Chaudhry severing their and promote to filaments 2009) al., Quintero-Monzon ADF/cofilin-et 2002; the Yahara, to and binds (Moriyama HFD complex The G-actin bottom). a 1B, forms (Fig. 2005) Yusof HFD al., 2003; et al., the et that (Ksiazek dimer anti-parallel show associated laterally analyses Structural (HFD). domain bundle stable a antiparallel of six composed of of is self-oligomerization region N-terminal or the of cyclase Most adenylyl CAP. to might solution binding coiled-coil been upon a in not form Therefore, has far. unstructured formation thus coiled-coil demonstrated is and structurally 2004) region 2009). al., self- et al., N-terminal for (Mavoungou required et this is (Quintero-Monzon and However, Srv2/CAP 1998) of al., that enzyme oligomerization et an (Nishida cyclase, adenylyl cAMP to produces Srv2/ binding yeast for of sufficient region 1A). this is 1A); (Fig. CAP (Fig. coiled-coil 2010) a section. form next to al., predicted the in et discussed are (Hliscs CAP of C-CAPs orthologs of and sequence so-called Isoforms C-terminal the the have CAP CAP, only single and protozoa a CAP1 isoforms, Parasitic only CAP CAP2. is have two which have species vertebrates 1A), Most although (Fig. isoform, section. domains this and in motifs discussed acids, distinct amino several 450–550 of has consists and CAP species, the on Depending CAP of organization Domain ntecnrlrgo fCP hr r w rln-ihregions proline-rich two are there CAP, of region central the In ( acids amino N-terminal most The a hlcs(i.1)ta r emdhlclfolded helical termed are that 1B) (Fig. -helices , 0rsde)o A are CAP of residues) 40 , 0poieresidues, proline 10 3249 Journal of Cell Science mn cd oti ieiainmtf nwhich C-terminal in most motif, The dimerization right-handed a 1C). of (Fig. contain coils 2004) acids six amino al., into et arranged (Dodatko are which pce n r otpoal rsn nalekroe Fg 2; (Fig. is eukaryotes CAP all of structure in domain The present S1). Table probably material supplementary most eukaryotic are representative all and almost species in identified been have nomenclature CAPs and orthologs 2013; isoforms, al., CAP 2013). et Ono, the and Makkonen of Nomura 2010; 2004; independently al., al., G-actin et The et to Mattila Architecture 1998). (Chaudhry binds al., Modular domain CAP et WH2 Simple of (Schultz domain the database CARP (SMART) in Tool and domains al., CAPs Research termed et (CARP) currently (Dodatko are RP2 (RP2) domains and homologous protein C the 2 2004); cofactor pigmentosa in tubulin-binding present retinitis including is C- X-linked proteins, that motif the of sequence number addition, a a contains In CAP of bottom). half 1C, terminal (Fig. dimer strand-exchanged a in participate 1 dynamics). Box actin (see in 2010) nucleotides of of al., exchange significance et actin-bound G- nucleotide the (Chaudhry the for for below to in 1A) described preference binds role (Fig. as Aldrich crucial Srv2/CAP strong G-actin, a domain Wiscott yeast has a and of a exhibiting nucleotides (WH2) WH2 is without 2002). 2 CAP actin al., of homology et region Also (Paunola protein 1997). central Drubin, the yeast and Syndrome of Lila in P2 1996; to that al., located 1996), binds et al., (ABP1) et 1 (Freeman (Freeman protein Srv2/CAP al., CAP1 actin-binding human kinase yeast et of tyrosine the (Makkonen P1 the of of the CAP1 domain to mouse (SH3) binds an 3 Abl of homology profilin, CAP and Src instance, Srv2/CAP The 2007) for 2013). yeast For al., of P2. et partners P1 or (Bertling to interaction P1 binds protein, either Several actin-monomer-binding to bind residues. selectively proline of 3250 D–-ci antrcag tef hc rvnsthe prevents which itself, available, recharge is ATP cycle. treadmilling free newly maintaining cannot no thus, ‘recharge’ when The and, can ADP–G-actin However, ATP cycle. F-actin. ADP–G-actin for by treadmilling ADP present, the at exchanging bound is rapidly primarily by ATP predominantly itself free are occurs When monomers ADP. ADP actin into hydrolysis depolymerized whereas ATP actin- G-actin, at of of primarily exchange occurs Furthermore, nucleotide it treadmilling. bound therefore undergo and affinity, not F- equal the and nearly does with G- to ends at binds of barbed ADP–G-actin ratio and However, polymerizes pointed the treadmilling. called in and is change which apparent end actin, an a constantly without pointed actin When end F-actin, the barbed end. of from end pointed pointed depolymerizes the the with to constant ATP–G-actin dissociation the for than below of falls end affinity ATP–G-actin barbed of for concentration higher the (minus) to pointed with competent binds the ATP–G-actin F-actin properties, ends. more different (plus) barbed with and ends is (F-) two filamentous has (ATP–G-actin) Polymerized actin ADP–G-actin. monomeric actin both than in polymerization ATP-bound (G-) properties its depolymerization. globular affects and strongly the and actin ADP, polymerization or of ATP of status molecule one nucleotide to binds molecule actin One ADP) and dynamics (ATP filament nucleotides actin adenine in of Role 1. Box h -emnlhl fCPi otycmoe of composed mostly is CAP of half C-terminal The ora fCl cec 2 (15) 126 Science Cell of Journal b seto eodCPmlcl,rsligi a in resulting molecule, CAP second a of -sheet b b b -strands, -helixes -strands , 35 Nmr ta. 02 n omsl A CS2 Nmr and (Nomura (CAS-2) CAP nonmuscle a and 2012) al., et (Nomura whether unknown Similarly, nematode properties. currently biochemical the of different is have regulator CAP2 it and crucial However, CAP1 a below. muscle), discussed be skeletal and In as to (heart 1995). muscle shown striated al., in et been assembly sarcomere Swiston has 2004; al., CAP2 et particular, (Bertling testis skeletal heart, and brain, muscle, muscle in skeletal expressed predominantly in is except CAP2 – whereas In expressed patterns. widely expression is are different CAP1 2). exhibit mammals, which (Fig. and 1994), sequence al., (Swiston acid plants et CAP2 amino Yu and green 1995; CAP1 al., isoforms, and et CAP nematodes two have vertebrates, Vertebrates are isoforms CAP in only multiple However, invertebrates 2). present many (Fig. and N- gene CAP protists an one Fungi, have contains 2010). CAPs al., and of domain et HFD tree) (Hliscs the to phylogenetic homologous not the see is that 2, region in terminal (Fig. CAP domain atypical CARP the the contains that protein CAP-related amla A ooo n rgnlynmdMCH1 a named as originally A cloned and 1993). was al., 1 CAP1 CAP1 et homolog porcine Rat (Zelicof is CAP 1992). ASP-56 Mann, mammalian partial that and and shown protein, (Gieselmann from have actin-monomer-binding isolated sequences and an been peptide identical, as has are ASP-56 platelets Srv2 Srv2/CAP. pig Srv2 and as name CAP designated 1990). yeast often of al., the suppressor et a explaining as (Fedor-Chaiken thus also and RAS2(V19), 1990) al., hyperactive CAP et adenylyl-cyclase- an used. (Field as protein been yeast associated budding also in have identified originally names was alternative several these However, in expressed also a are manner. in dynamics tissue-specific filament 2006), actin modulate to these al., cooperate regulators of actin isoforms et specific Kovar that 2007; 2007; Polet suggesting organisms, al., multicellular 2000; (Ono, et (Jockusch al., ADF/cofilin profilin and et including 2011) al., regulators, et actin Poukkula isoforms their other Multiple isoforms, understood. of well CAP not of are expression Thus, differences determined. tissue-specific functional been the not than have other S1), differences Table functional material supplementary their 2; but (Fig. plants green identified several been have in isoforms CAP several addition, In 2013). Ono, rln-ihsqec tteNtriu,btohrCCP onot do 2010). C-CAPs al., other et but (Hliscs N-terminus, the al., at et sequence proline-rich (Hliscs motif only 1A). dimerization (Fig. protozoa the and 2010) in domain CARP C-CAPs the However, have species. among conserved oii nodrt euaetednmc fatnflmnsas filaments actin of dynamics ADF/ the with 3. regulate Fig. cooperate to in shown AIP1 regulatory order and actin in profilin other cofilin CAP, Several including G-actin. ADF/cofilin proteins inhibits of and filaments. ADP exchange by actin bound nucleotide molecule actin of an to turnover binds and preferentially polymerization persistent actin can of promote promotes is rounds ADF/cofilin new can for F-actin by and G-actin of Because disassembly pool F-actin a a F-actin ends. supply severs in of filament enhancement F-actin from the ADF/cofilin stable, and G-actin 1:1. G-actin promotes of to of that dissociation binds ratio It protein filaments. molar actin-regulatory actin of an turnover is (ADF)/cofilin ADF/cofilin factor depolymerizing Actin 2. Box yls-soitdpoeni h rgnlnm o CAP. for name original the is protein Cyclase-associated .elegans C. Leishmania esmnamajor Leishmania a ohamsl-pcfcCP(CAS-1) CAP muscle-specific a both has Drosophila and Trypanosoma A eewsidentified was gene CAP a nte ogfr fa of form long another has , 0 dnia ntheir in identical 60% -Ashv a have C-CAPs Journal of Cell Science ci-euaoyfntoso CAPs of in functions proteins Actin-regulatory these for name cyclase-associated common literature. a exceptions, the as of (Waddle these used most is proteins from CAP capping Apart or protein actin 1993). of al., subunits et encode ‘ that because genes 2012), al., et (Nomura bto)aeson oain fN n -emn r niae.The (Schro indicated. PyMOL are with C-termini produced and were dimers N- graphics and of molecular (top) Locations monomers shown. of are Structures (bottom) (C). 1K8F) number accession 2000). tutrso h eia odddmi HD PoenDt akaccession Bank Data (Protein and (HFD) (B) domain 1S0P) folded number helical the ( of domains. structures functional below actin-regulatory shown and are partners functions interaction Representative protozoans). in (CAP n otlo 02.Tourltdpeoye a edtce in detected be cytoskeletal can phenotypes their unrelated (Hubberstey Two eukaryotes 2002). instead, among Mottillo, a various conserved and but, only be to to in organisms; appears specific function of CAPs is function number of signaling limited this studies that the suggest of pathway, component species a signaling as discovered Ras–cAMP originally was CAP actin Although the of regulators as cytoskeleton CAPs of functions Conserved and 2002) to al., allelic et is Wills and 2000; flies al., mutant et (Baum of screening the following CAP. of Structure 1. Fig. B A N CAP C-CAP C HFD N C dnllccaeProfilin Adenylyl cyclase Coiled coil N C N .elegans C. F-actin: severing HFD b A ee eenamend were genes CAP -sheet/ ( A oanognzto fCPadC-CAP and CAP of organization Domain ) N F-actin: severing nucleotideexchange G-actin: monomersequestration b hlx(AP oan(rti aaBank Data (Protein domain (CARP) -helix C WASP homology2 Proline rich 1P2 P1 Abl C cap CARP domain a led enue for used been already had ’ ABP1 N N C nucleotideexchange G-actin: monomersequestration B N , C c up act ibndarmo the of diagram Ribbon ) CARP domain dne,LLC). ¨dinger, C C cas-1 Bnaie al., et (Benlali Dimerization motif C and capulet N cas-2 eei sashv rvddsldeiec htCP are, these CAPs Thus, that cytoskeleton. 1992). evidence actin the al., solid of et regulators provided conserved (Matviw indeed, have humans a assays and demonstrated genetic 1993) from have al., CAPs et studies of genetic function edodes Similar actin-regulatory actin-regulatory 1992). (Kawamukai conserved the CAPs al., among that conserved et Ras- evolutionarily the suggesting is not function but phenotype, phenotype budding actin-related dependent Srv2/CAP-deficient the in suppress can yeast, from actin yeast fission CAP normal heterologous e.g. a species, of of al., other et expression loss (Vojtek the bundles the actin Furthermore, abnormal 1991). distribution, of formation the actin a and cables with polarized of associated of half are morphological C-terminal lack cells The a Srv2/CAP-deficient 1991). in al., and abnormalities et half by (Gerst N-terminal suppressed respectively an independently Srv2/CAP, be of 1990; could expression These al., the 1990). et al., et (Fedor-Chaiken Field signaling abnormalities Ras–cAMP morphological defective and cells: yeast Srv2/CAP-deficient al iceia tde nCP ugse htCP are CAPs that suggested CAPs on studies biochemical and Early sequestration exchange monomer nucleotide – of G-actin enhancement on CAP of Effects endmntae o Asfo udn es Femne al., et has (Freeman yeast activity budding 1995), from This CAPs G-actin. for these demonstrated of been of polymerization basis actin the spontaneous dynamics. on cell actin in revised and CAPs be for genetic to functions early identified need recently some may filaments. of studies actin of biology interpretations dynamics fulfill actin the the CAPs promoting that al., Therefore, in prevent revealed et roles have active (Freeman studies more ends that recent filament However, from 1995). proteins elongation and nucleation sequestering actin-monomer oatnpthsi es Ll n rbn 97 n othe to and 1997) Drubin, and (Lila yeast motile of is in edges localize leading patches CAPs is that 1983). actin which concentration Bamburg, to and G-actin, 30 a (Heacock of of level cells at high non-muscle sequestration a unclear cells at to maintained is in generally contribute it present to determined, a is been sufficient in not CAP present cellular the has is whether As CAPs G-actin. it of of that when concentration to G-actin equimolar is sequesters that the concentration At CAP 2002). state, used Yahara, are and steady G-actin (Moriyama and amounts CAP1 stoichiometric when at human G-actin, addition it with monomer that when compared inhibits shown ends amounts but barbed sub-stoichiometric was to in it G-actin present of is This because addition studies, end. the accelerates these G- barbed CAP1 to in Srv2/CAP the of used ratios to different actin to G-actin specifically owing be Srv2/CAP of might yeast discrepancy incorporation al. that et the reported Mattila either 2004) inhibits whereas to filaments, al., somewhat actin et G-actin of (Mattila is of ends barbed incorporation elongation or that the reported pointed actin inhibits 1995) al., on Srv2/CAP et (Freeman yeast CAP al. et of Freeman controversial; effect platelets pig The 2013), and 2010). 2013) Ono, (CAP2) al., humans et and 1992), (Peche Mann, Nomura and 2012; (Gieselmann (ASP-56/CAP1) 2007), al., et al., (Nomura et (Chaudhry hrfr,telclcnetaino A ol esufficiently be could CAP of 1996). concentration al., local et Zelicof the 2000; Therefore, Field, and (Freeman cells mammalian A id oGatna oa ai f11adihbt the inhibits and 1:1 of ratio molar a at G-actin to binds CAP sitk uhom Zo ta. 98,rt (Zelicof rats 1998), al., et (Zhou mushroom) (shiitake Dictyostelium yls-soitdpoen3251 protein Cyclase-associated Dictyostelium Gtwl ta. 1996), al., et (Gottwald Cryptosporidium .elegans C. Gtwl ta. 96 and 1996) al., et (Gottwald CCP Hic tal., et (Hliscs (C-CAP) , CS1adCAS-2) and (CAS-1 0 fttlatnin actin total of 50% Arabidopsis Lentinus Journal of Cell Science xhnead hrfr,peetti rcagn’process. ‘recharging’ this nucleotide prevent this therefore, inhibit 1985) and, (Nishida, exchange ADF/cofilin G-actin-binding and several 1992) However, thymosin 1986; 1). Pollard, including (Box 1993; proteins, 1992) al., al., et De Kinosian et 2010; of 2001; Pollard Carlier, polymerization Pollard, and and the (Bugyi Cruz and end La filament barbed actin the from the ATP–G-actin from of the ADP–G-actin end of pointed by cycle, depolymerization hydrolysis the biased ATP treadmilling’ the and actin- drive ATP ‘actin with F-actin important G-actin the most of recharging its During constant be effect. might which regulatory sequestering 3), (Fig. actin-monomer nucleotides important the indeed is CAP whether it of sequences. However, function numbers locations. unclear accession these database at for monomers remains S1 actin Table sequester material supplementary to See high left. the on shown as classified and eukaryotes. 1994) in al., CAPs et of (Thompson tree Phylogenetic 2. Fig. 3252 358.0 A loehne h aeo xhneo G-actin-bound of exchange of rate the enhances also CAP 350 ora fCl cec 2 (15) 126 Science Cell of Journal atypical CAP Protozoan 300 Protozoan C-CAP Vertebrate CAP1 b Invertebrate CAP Plant/algal CAP 250 GlshitCemn tal., et (Goldschmidt-Clermont 4 Amino acidsubstitutionsper100residues Invertebrate CAP Leishmania major nvivo in Fungal CAP Protist CAP 200 mn cdsqecso A-eae rtisfo ersnaieognsswr nlzdb lsa W Clustal by analyzed were organisms representative from proteins CAP-related of sequences acid Amino . Trypanosoma cruzi Trypanosoma cruzi Leishmania major Vertebrate CAP2 CAP (protozoa) 150 C-CAP (protozoa) C-CAP2 (protozoa) C-CAP (protozoa) Plasmodium falciparum 100 90 ihd,18)(i.3 n,teeoe nacsactin enhances thymosin therefore, of and, presence Korn, 3) the (Fig. and in G- Mockrin turnover 1985) at 1991; Nishida, al., exchange 1980; et nucleotide (Goldschmidt-Clermont the actin promotes catalytically Profilin r2CPdfcetyatclscnb upesdby suppressed in However, be activity 1991). nucleotide–exchange this al., lack can profilins et algae, (Vojtek and of plants cells profilin phenotypes cytoskeletal of a the overexpression yeast Such that 3). showed (Fig. that Srv2/CAP-deficient by 2009) study suggested was early al., Nomura profilin an and 2002; 2003; et CAP between Yahara, al., Quintero-Monzon similarity actin and functional et 2012; Moriyama (Balcer thus, al., 2007; ADF/cofilin et and, al., of et G-actin presence Chaudhry of the of capable and in is exchange CAP turnover (Blanchoin Similarly, nucleotide 1998). ADF/cofilin al., enhancing or et Didry 1993) 1998; Pollard, Carlier, and Pantaloni Danio rerioD Drosophila melanogaster Toxoplasma gondii a C-CAP (protozoa) Xenopus laevis ni Crassostrea gigas Homo sapiens Anolis carolinensis 50 Xenopus laevis Rat tus norvegicus tus Rat Mus musculus Gallus gallus Gallus gallus Branchiostoma floridae Anolis carolinensis Homo sapiens Mus musculus Rat tus norvegicus tus Rat Danio rerio Xenopus laevis o Gossypium hirsutum Capitella teleta Ciona intestinalis r Ixodes scapularis Zea mays Arabidopsis thaliana Cryptosporidium parvum e Oryza sativa Strongylocentrotus purpuratus Hydra viridissima Zea mays Polysphondylium pallidum Dictyostelium fasciculatum ri Dictyostelium discoideum Oryza sativa Acanthamoeba castellanii o Oryza sativa Oryza sativa CAP1 (fish) CAP1 C Caenorhabditis elegans A P CAP2 (fish) CAP2 1 Caenorhabditis elegans CAP2 (chicken/ bird) CAP2(chicken/ CAP2 (corn/plant) CAP1 (chicken/ bird) CAP1 (chicken/ CAP1(human/mammal) Lentinula edodes CAP1 (mouse/ mammal) (mouse/ CAP1 (() Chlorella variabilis CAP2(human/mammal) Saccharomyces cerevisiae Saccharomyces CAP1a (frog/ CAP1a amphibian) CAP2 (mouse/ mammal) (mouse/ CAP2 CAP1 (corn/plant) fish CAP1b (frog/ CAP1b amphibian) CAP2 (frog/ amphibian) C-CAP (protozoa) 0 CAP (polycheteworm/annelid) CAP2 (rice/plant) Schizosaccharomyces pombeSchizosaccharomyces Candida albicans CAP (oyster/mollusc) CAP1(lizard/reptile) Aspergillus nidulans CAP1 (rat/mammal) CAP1 Entamoeba histolytica ) CAP3 (rice/plant) CAP2(lizard/reptile) () CAP1 (rice/plant) CAP (ascidian/Urochordata) CAP2 (rat/mammal) CAP2 CAP(tick/arthropod) CAP4 (rice/plant) CAP (hydra/hydrozoa) Capulet/Act up(insect/arthropod) CAP (cotton/plant) CAP1 (rockcress/plant) CAP (amphioxus/Cepharochordata) C-CAP (protozoa)

CAP (slimemold) CAP (slimemold) CAP (mushroom) CAP CAP (slimemold) CAP (amoeba) CAS-1 (nematode) CAP (greenalgae) CAP (seaurchin/echinoderm) CAP (infectious CAP yeast) CAS-2 (nematode) CAP (mold) b CAP (amoeba) Crire l,1993; al., et (Carlier 4 Srv2/CAP (buddingyeast) CAP (fission CAP yeast) Journal of Cell Science Mrym n aaa 02 uneoMno ta. 2009). al., et Quintero-Monzon 2002; filaments Yahara, actin and and of 3) turnover (Fig. (Moriyama complex ADF/cofilin-mediated ADF/cofilin-actin the the to augments binds CAP of in half turnover a actin in regulate function al., CAP to et cells. and manner (Wen mammalian profilin hierarchical profilin whether or yeast unclear than redundant is rates it faster but much 2008), exchange For to nucleotide organisms. G-actin the other between of enhances in relationship understood profilin well mammalian functional not instance, is the profilin and and However, Srv2/CAP CAP of 3). al., P1 (Fig. et (Bertling to yeast 2007) (Mattila in binds localization yeast profilin actin polarized in addition, in collaborates proposed In ATP–G- 2004). been of sequential al., has incorporation ADP/ et barbed-ends) the a (for actin (for CAP to Thus, profilin actin by and monomers 2010). exchange) actin ATP al., of to bound mechanism et is processing ADF/cofilin (Chaudhry when fails and exchange ADP–G-actin 2008) than nucleotide al., et activity enhance Wen 1998; nucleotide-exchange to al., et weaker (Eads much profilin mammalian Yeast a 2002). Yahara, has and ADP– Moriyama profilin to 2004; binding al., et for Carlier, (Mattila affinity ADF/cofilin G-actin high with and relatively competes a effectively (Pantaloni with and ADP–G-actin to ATP–G-actin which binds CAP profilin, to 1993), unlike in However, binds G-actin 2007). for 1996) preferentially exchanger al., al., nucleotide et et known (Chaudhry Perelroizen only plants 2001; the al., is et CAP Kovar and 2000; al., et (Kovar a form. only G-actin-bound simplicity, a for as but, binds shown form CAP is oligomeric that CAP molecular an note monomeric the in Also that hypothetical. monomers Note is actin 2013). oligomer to al., CAP ADF/cofilin- et the between (Elam of boundary segments organization the bare at the them and severs bound binds and cooperatively filaments ADF/cofilin AIP1. actin and are to profilin activities by These exerted those promotes (bottom). to also filaments similar CAP actin (top). ADF/cofilin-bound exchange of nucleotide severing its promotes ADF/cofilin, and CAP, (right) by dynamics AIP1. filament and actin profilin of Regulation 3. Fig. nhmnCP n es r2CP F nteN-terminal the in HFD Srv2/CAP, yeast and CAP1 human In (+) end Barbed CAP oligomer actin ATP- actin ATP- ADP(P actin A optswt D/oii o idn oG-actin to binding for ADF/cofilin with competes CAP Severing Nucleotide exchange i ADF/cofilin ) ADP ATP Severing Depolymerization actin ADP- AIP1 CAP actin ADP- Depolymerization (–)end Pointed Profilin HFD ADF/cofilin CAP CARP actin ADP- lhuhteCR oani ufcett rmt the ADF/ promote when exchange to nucleotide 2013), 1995). facilitate sufficient al., to al., et necessary is (Makkonen et is its ADP–G-actin WH2 domain (Amberg of disrupt exchange – CARP – yeast nucleotide 4 binding in the CARP and Srv2/CAP for 2 Although sites subdomains with candidate its interaction has the in G-actin are mutations on which determined, site a CARP-binding been in G-actin a not to 3 Although bind and might manner. 1 was CAP subdomains similar of its WASP, WH2 between as cleft and a 2007), such N- at (Dominguez, proteins, G-actin An to other al., bind G-actin. from to et contact found WH2 Peche of separately 2004; part al., they terminal et that Mattila suggesting 2013; al., and et 2013), al., 1995), (Chaudhry et al., G-actin Makkonen to et independently 2010; (Freeman that bind G-actin half CARP CAP of and of molecule C-terminal WH2 half one C-terminal its to The bind 1A). in can (Fig. reside CARP and CAP WH2 contains of activities al., exchange et (Chaudhry below. severing a discussed has filament is instead, actin which but, 2013), G-actin in and function ADF/cofilin required separate of not is recycling HFD the that ADF/cofilin-actin shows for the study recent of a dissociation However, the complex. active in an HFD for of evidence as involvement interpreted originally were results These ceeaino h uloieecag fGatnb A is CAP the by G-actin for of basis exchange structural unknown. nucleotide largely the the ADF/cofilin Nonetheless, of with acceleration compete binding. WH2 to same able 2011), G-actin be the Holmes, to for CAP share and for needed (Dominguez WH2 be G-actin and might on ADF/cofilin site Since Nomura binding 2010; 2013). al., et Ono, (Chaudhry and ADP–G-actin to bound is cofilin rti,opst otelcto fisN n C-termini. and N- its of location HDF the the still of to CAP surface the of to opposite mapped HFD been protein, the have HFD Srv2/CAP in by yeast residues severed of surface important are Functionally unclear. filaments remains mechanism actin the However, how 2013). in al., of et study Srv2/ (Chaudhry of genetic AIP1 half a and N-terminal the CAP which Indeed, of ADF/cofilin-bound functions 3). 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CAP al., et whether Sultana 2009; al., et Sultana smnindaoe A lobnst h H oano the of domain SH3 the to binds also CAP above, mentioned As arc ahgn Zo ta. 02.In 2012). al., et (Zhou pathogen) rice (a Wn ta. 00 o ta. 00 and 2010) al., et Zou 2010; al., et (Wang Drosophila Dictyostelium Drosophila i n v ernldvlpet A (Capulet/Act CAP development, neuronal ´ i v nvivo in dze l,21)adeedevelopment eye and 2011) al., et ndez o Gtwl ta. 96 ogle al., et Noegel 1996; al., et (Gottwald ntecneto ci filament actin of context the in ucin fCPta aenot have that CAP of functions Drosophila A lodisturb also CAP Dictyostelium Magnaporthe Drosophila Drosophila Candida , Journal of Cell Science ta. 03.Kokono A lordcstert fcell of rate the reduces also CAP of Knockdown 2003). in unknown al., inhibits lamellipodia strongly et an of CAP Yahara, of formation in and Knockdown 1999). the Moriyama part al., 2000; et N-terminal the Noegel Field, of 2002; its and edge leading through (Freeman the mechanism mediated to CAP is Zelicof of 2002; localization cell The Yahara, 1996). and al., Moriyama et 2000; Field, and Freeman ta. 03.Itrsigy h xrsino os A2is CAP2 mouse of expression the 1995), during Interestingly, al., induced prominently 2013). et mammals Swiston al., 2007; of et al., muscles et ( Peche cardiac frogs 2004; certain al., and in et levels For skeletal (Bertling high units. contractile at including basic expressed tissues, the is – CAP2 is sarcomeres vertebrate isoforms example, of CAP assembly two the role the in essential an of has and muscle the one striated in expressed vertebrates, predominantly an and However, nematodes muscle In suggesting striated tumorigenesis. in organization further Sarcomere unknown. in is 2012), interaction this CAP1 of al., significance functional of et 1 of domain involvement RING (Woods types BRCA1-associated interacts certain suppressor CAP1 (BARD1) that tumor for shown has the study target with recent a therapeutic a addition, as In in or serve cancer. might overexpressed CAP marker al., established, levels be be diagnostic et CAP can between Shibata phenotypes to al., correlation cancer 2013; functional and et found a al., if (Patsialou cancer been et Therefore, 2006). cancer (Effendi has pancreatic breast carcinoma CAP2 in hepatocellular and and between 2009) overexpressed al., 2012), correlation is phenotypes. et cancer CAP1 a of (Yamazaki occurrence instance, suggesting and in CAP For cancer, of overexpressed levels of are increased isoforms types CAP several Mammalian cells. cancer whether unknown defects. is cytokinesis Field it by but 1990; caused 1992), are al., al., et these et Kawamukai 1990; (Fedor-Chaiken al., under et conditions or temperature high nutrient a has at certain defects structures growth causes cytokinetic a the yeast other of fission Deletion of or localization reported. furrows been However, suggestive cleavage not 1999). to cells, al., CAP et of multinucleated (Noegel defect of cytokinesis number increased understood. fully not regulates still it aspects exactly is different how migration in but cells; cell roles motile has within dynamics it actin that of (Freeman suggesting fibroblasts 2000), mammalian Field, in and fibers lamellipodial stress of cell formation enhances the of during cortex posterior dynamics the CAP to migrating filament localizes also that CAP actin However, migration. promoting 2009). suggest al., by et protrusion Yamazaki reports 2004; al., These et (Bertling cells mammalian in migration ulmc i ale hnwl-yemc n hwapeoyethat CAP2- phenotype 2007). a show al., and et mice wild-type (Peche than filaments earlier thick die which mice the null M-lines, of center the the skeletal to at localizes are differentiated it cardiomyocytes, in and myotubes whereas, and cardiomyocytes, myoblasts skeletal in in cytoplasm embryonic the localized in is diffused and CAP2 nucleus muscles, the cardiac and skeletal mammalian 2007).In al., et Terami 2008; al., et for (Christoforou development marker cardiac a is CAP2 that indicating cardiomyocytes, into cells stem elmgainadctknssaeaernl euae in regulated aberrantly are cytokinesis and migration Cell in levels protein CAP of Reduction Xenopus Dictyostelium Dictyostelium Wlnk ta. 09,adzbaih(Effendi zebrafish and 2009), al., et (Wolanski ) el Nee ta. 99 n promotes and 1999) al., et (Noegel cells nvitro in Nee ta. 99 n cultured and 1999) al., et (Noegel CAP Drosophila ifrnito fembryonic of differentiation Dictyostelium eei udn es or yeast budding in gene 2cls(Rogers cells S2 ed oan to leads A1i cieyivle nteAp/-eedn actin Arp2/3-dependent the in involved pathway actively that complex suggesting Arp2/3 is defects, the CAP1 morphological in enhance mutations CAP1- synergistically The and bundle epidermis. of actin and mutation and hairs elongation 2007), null root al., in reduced et disrupted (Deeks is and hairs organization root statue and CAP1-null tubes addition, reduced pollen In including not 2003). but defects, al., size et in reduced (Barrero to mutations However, due cells primarily 2002). of is number that al., in size et resulting organ reduced cells, (Barrero of petioles number of overexpression and and size leaves the smaller in of reduction Overexpression a 2007). causes al., functionality nucleotide this et G-actin possess not of (Chaudhry do enhancer profilins known plant only because the exchange, is CAP plants, In development Plant grgts(ouae l,21) nCS1nl om,the worms, severe CAS-1-null In exhibit 2012). and al., stages actin et of larval formation (Nomura with early aggregates filaments actin to muscle of embryonic disorganization organization lethal homozygous actin late are sarcomeric worms at CAS-1-null for 2012). the al., required to et is (Nomura localizes it and where muscle M-lines, striated in expressed predominantly diseases. heart with associated are that lesions genetics human molecular Therefore, target 2009). of that approaches al., regulation et (Bremer including phenotypes the defects clinical heart several in cause region this role at CAP2deletions its human The ( as understood. gene not well are filaments as actin sarcomeric significance, M-line, the its to localizes it and which in by organization mechanism sarcomere the muscle, for striated important communication). thin clear is is M-lines, CAP2 it although mammalian Thus, disturbed that 2013). al., personal with et (Peche Z-discs disorganized and fromfilaments are muscles cardiac Pennsylvania, Field, mice and Jeffrey CAP2-null skeletal in 2013; myofibrils al., the of Furthermore, et (Peche function University heart including impaired fibrosis, cardiomyopathy, increased atrium, and and dilated ventricle dilated with with heart enlarged associated typically is oprt orglt acmr sebyi amla muscle. be mammalian will in assembly specifically it sarcomere CAP2 regulate Therefore, and to 2012). cofilin-2 cooperate whether al., determine et to (Agrawal interesting muscle myofibrils skeletal of human maintenance in impaired in show Mutations mice 2002). cofilin-2-null and al., et Vartiainen ( cofilin-2 1994; and actin-regulatory al., assembly et specific (Ono the ADF/cofilin a muscle-specific a is that require cofilin-2 Mammalian muscle-specificmechanism. sarcomeres suggests of of dynamics set maintenance a actin of of presence regulators The 2010). (Ono, myofibril dynamic maintain integrity to a disassembly and requires assembly sarcomere actin muscle of striated regulation in promote filaments actin Sarcomeric to UNC-60B muscle. striated with in organization cooperates in al., studies strongly of CAS-1 UNC-60B. et genetic muscle of function the regulator Ono correct CAS-1-null for Thus, 2003; required in crucial is CAS-1 al., mislocalization that a suggests et its also and (Ono 1999), organization is actin UNC-60B these sarcomeric to aggregates. mislocalized is actin UNC-60B ADF/cofilin muscle-specific ntenematode the In hs A sacnevdrgltro acmr organization. sarcomere of regulator conserved a is CAP Thus, CAP2 CFL2 slctda h hoooergo p23 and 6p22.3, region chromosome the at located is ) Arabidopsis as eaiemoah Arwle l,2007), al., et (Agrawal myopathy nemaline cause ) Arabidopsis yls-soitdpoen3255 protein Cyclase-associated .elegans C. as ubro developmental of number a cause CAP2 .elegans C. A1i oac lnslast a to leads plants tobacco in CAP1 h A sfr A- is CAS-1 isoform CAP the , ih eelseii genetic specific reveal might rvd vdnethat evidence provide Arabidopsis CAP1 Journal of Cell Science i.4 ilgclfntoso CAP. of functions Biological 4. Fig. relationship also functional is the It proteolysis. understand by better controlled is kinase to CAP through important of the a regulated that level of indicating substrate 2008), protein be al., intracellular et an (Cauwe can metalloproteinase also matrix is of CAP CAP1 pathways. University of signaling Field, localization activity Jeffrey that and Zhou, suggesting and communication), (Guo-Lei personal University, Pennsylvania, phosphorylated State poorly is are 1), Arkansas CAP1 regulated, (Fig. is CAP Mouse activity to bind CAP understood. to which known by Despite are mechanisms, conditions. proteins the several these agent that under fact anti-tumor CAP1-mediated induced the that the is suggesting reorganization with 2012), al., actin al., treated et et of macrophages (Oliveira (Martins-de-Souza functions lapachol in patients described, in and schizophrenic reported not 2010) been actin of has far brains have CAP1 require of so the upregulation studies that example, these, For high-throughput processes for CAPs. Some hints diverse provided 4). many (Fig. to in expected reorganization are involved they thus, of are dynamics; be CAPs in actin distribution that suggest of roles organisms wide regulators and common active types The cell exerts different dynamics. in CAP CAPs filament that actin revealed promoting have studies Recent function. Conclusions extracellular erythematosus an al., has et lupus also (Kinloch CAP1 arthritis that systemic rheumatoid suggesting and 2005), with 2000) al., et patients an (Frampton as identified in pro- been are they has autoantigen exactly CAP1 cofilin how Intriguingly, and unclear apoptosis. cofilin CAP1 apoptosis remains promote it that that of promotes although suggesting noting proteins, and 2003), execution apoptotic worth mitochondria al., is et the the It (Chua to promotes 2008). translocates al., the further also et to upon (Wang it translocates addition, apoptosis CAP1 where In mammalian trafficking. mitochondria apoptosis, in membrane of system in induction endo-lysosomal involved essential the is widely of CAP Theurkauf, functioning that or shown Dictyostelium correct and endocytosis been the has Stevenson in it for 2002; recently, as More Mottillo, such 2000). and functions, (Hubberstey other has Drosophila also CAPs CAP of functions biological Other elucidated. same been isoforms, the not CAP have in multiple differences have functional involved their Plants are but 2007). Arp2/3 al., et and (Deeks CAP1 process that or regulation, 3256 Cancer? Cytokinesis APsgaigKinasesignaling cAMP signaling Organ/tissue development ora fCl cec 2 (15) 126 Science Cell of Journal Cell migration eeomn,a icse nerirreviews earlier in discussed as development, Slaae l,20) ugsigta A is CAP that suggesting 2005), al., et (Sultana (CAP) Cyclase-associated protein Actin cytoskeletal Apoptosis dynamics Neuronal axongrowth Sarcomere organization Vesicle trafficking ale,M . en . igr .J,Lnat .adPnaoi D. Pantaloni, and M. Lenfant, J., K. Rieger, C., Jean, F., M. Carlier, F. M. Carlier, and B. Bugyi, D. T. Pollard, and L. Blanchoin, and M. Salminen, T., Matilainen, K., P. Mattila, P., Hotulainen, E., Bertling, H. Uchimiya, and S. Yamamura, M., Umeda, A., R. Barrero, rmr . comn,J,Nordenskjo J., Schoumans, A., Bremer, P. Lappalainen, and L. B. Goode, K., P. Mattila, O., Quintero-Monzon, E., Bertling, E. J. Treisman, and J. D. Hazelett, I., Draskovic, A., Benlali, N. Perrimon, and W. Li, B., Baum, N. Perrimon, and B. Baum, H. Uchimiya, and S. Yamamura, M., Umeda, A., R. Barrero, and E. J. Heuser, J., Kugler, E., Smith, A., A. Rodal, L., A. Goodman, I., H. Balcer, D. Botstein, and E. Basart, C., D. Amberg, eelagetrcmlxt ftergltr ehns that mechanism regulatory the dynamics. of filament to likely actin complexity most governs greater are CAPs a on studies reveal controls further can CAP Thus, how filaments, dynamics. affect CAP actin actin may proteins of proteins. actin-regulatory disassembly other and actin-regulatory and assembly other both in and participate CAP between aw,B,Mres . a e te,P . rot . a es,I,Blockmans, Gue I., F., Aelst, Chaudhry, Van P., Proost, E., P. Steen, den Van E., Martens, B., Cauwe, gaa,P . rela,R . oca,K . etkr,V . Wallgren- L., V. Lehtokari, K., K. Tomczak, S., R. Greenleaf, B., P. Agrawal, References at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.128231/-/DC1 online available months. Health material 12 of Supplementary after Institutes release National for the PMC from in grant Deposited a AR48615). (R01 by supported is S.O. the of Funding reading critical communication for for Field results. Jeffrey unpublished Nomura and of Zhou Kazumi Guo-Lei and thanks manuscript, author The Acknowledgements gaa,P . oh,M,Svc . hn .adBgs .H. A. Beggs, and Z. Chen, T., Savic, M., Joshi, B., P. Agrawal, huhy . ite . aaio . uneoMno,O n od,B L. B. Goode, and O. Quintero-Monzon, L., Talarico, K., Little, F., Chaudhry, motility. cells. nonmuscle mammalian in dynamics actin induced P. Lappalainen, ai:psil mlcto nterglto fatndynamics. ATP/ADP actin the of by regulation 4 the beta in thymosin implication and G-actin possible between ratio: interaction the of Modulation short defects, heart including features abnormalities. dysmorphic eye and and neck, delay developmental with M. profilin. and 25111. (ADF/cofilin) actophorin Acanthamoeba interaction. profilin-Srv2/CAP of role 120 biological and Mechanism (2007). the 2334. in signaling Hedgehog restrict and shape cell disc. alter eye Drosophila to polymerization yeast. in actin and oogenesis Drosophila during polarity cell and size organ plants. to leading tobacco expansion transgenic cell in decreased reduction causes CAP Arabidopsis of expression division. and elongation cell plant for Cell necessary Plant cytoskeleton actin the regulates CAP Aip1. and profilin, cofilin, 2159-2169. complex, Srv2/CAP molecular-weight L. B. Goode, ilgcltre usrt fgltns B/MMP-9. gelatinase of substrate target G. biological Opdenakker, and D. USA uaino h F2gn noigteseea uceatnbnigprotein, actin-binding muscle K., skeletal S. the Maciver, encoding T., gene B. CFL2 Darras, cofilin-2. the al. G., of et N. mutation R. Laing, P. W., Dormitzer, Wallefeld, C., Pettersson, rspiaeihla cells. epithelial Drosophila vivo. in for actin yeast cofilin-2 of requirement demonstrates actin knockout with Cfl2 maintenance. disruption muscle mouse sarcomeric a progressive in by accumulations followed development myofibrillar eta oefrteW2dmi fSv/A nrcagn ci ooest drive vivo. to monomers in actin and recharging vitro in Srv2/CAP in of nucleotide turnover domain actin WH2 first the for role the central A as 1 actin. protein plant for cyclase-associated factor exchange Arabidopsis of Identification 1225-1234. , 20) nitrtta eeino .M ncrmsm ad62. associated 6p22.3 band chromosome in 7.1Mb of deletion interstitial An (2009). 90 5034-5038. , nu e.Biophys. Rev. Annu. m .Hm Genet. Hum. J. Am. 14 149-163. , 20) oriae euaino ci iaettroe yahigh- a by turnover filament actin of regulation Coordinated (2003). rn . o ish . lnhi,L n tie,C J. C. Staiger, and L. 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