Evolution of Modular Intraflagellar Transport from a Coatomer-Like

Total Page:16

File Type:pdf, Size:1020Kb

Evolution of Modular Intraflagellar Transport from a Coatomer-Like Evolution of modular intraflagellar transport from a coatomer-like progenitor Teunis J. P. van Dama, Matthew J. Townsendb, Martin Turkc,1, Avner Schlessingerc,2, Andrej Salic,d,e, Mark C. Fieldb,3, and Martijn A. Huynena,3,4 aCentre for Molecular and Biomolecular Informatics, Radboud University Medical Centre, 6500 HB, Nijmegen, The Netherlands; bDepartment of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and cDepartment of Bioengineering and Therapeutic Sciences, dDepartment of Pharmaceutical Chemistry, and eCalifornia Institute for Quantitative Biosciences, University of California, San Francisco, CA 94158 Edited by Russell F. Doolittle, University of California at San Diego, La Jolla, CA, and approved March 15, 2013 (received for review December 4, 2012) The intraflagellar transport (IFT) complex is an integral component NPC scaffold (2–4). This classification was based on sequence of the cilium, a quintessential organelle of the eukaryotic cell. The similarity of IFT subunits to the COPI-α and -β′ subunits, further IFT system consists of three subcomplexes [i.e., intraflagellar supported by secondary structure predictions. However, a full transport (IFT)-A, IFT-B, and the BBSome], which together trans- phylogenetic reconstruction and structural analysis of the IFT port proteins and other molecules along the cilium. IFT dysfunction complex has not been performed. Such an analysis is necessary results in diseases collectively called ciliopathies. It has been pro- because the abundance of the WD40 and TPR domains in non- posed that the IFT complexes originated from vesicle coats similar coatomer subunit proteins requires more than sequence similarity to coat protein complex (COP) I, COPII, and clathrin. Here we to establish a close phylogenetic relationship. Here, we have re- provide phylogenetic evidence for common ancestry of IFT subunits constructed the evolution of the IFT complex in detail, and and α, β′, and e subunits of COPI, and trace the origins of the IFT-A, provide phylogenetic evidence that the IFT complex is indeed IFT-B, and the BBSome subcomplexes. We find that IFT-A and the a sister structure to COPI. Analysis of the presence of the in- BBSome likely arose from an IFT-B–like complex by intracomplex dividual subcomplexes in currently living eukaryotes shows that subunit duplication. The distribution of IFT proteins across eukary- the presence and inferred order of the loss of subcomplexes otes identifies the BBSome as a frequently lost, modular compo- — mirrors their origin the IFT subcomplex that was added latest EVOLUTION nent of the IFT. Significantly, loss of the BBSome from a taxon is in evolution is the first to be lost. a frequent precursor to complete cilium loss in related taxa. Given the inferred late origin of the BBSome in cilium evolution and its Results frequent loss, the IFT complex behaves as a “last-in, first-out” sys- The known IFT system consists of three subcomplexes, IFT-A, tem. The protocoatomer origin of the IFT complex corroborates in- IFT-B, and BBSome, together comprising 33 subunits in Homo volvement of IFT components in vesicle transport. Expansion of sapiens (n = 7, n = 17, and n = 10, respectively). Twenty-one IFT subunits by duplication and their subsequent independent of these subunits can be divided into four groups based on ho- loss supports the idea of modularity and structural independence mology relationships and predicted structures (Fig. 1A). The first of the IFT subcomplexes. group (Fig. 1A, blue) comprises WDR19, WDR35, IFT140, IFT122, IFT172, and IFT80, whose domain structure resembles complex modularity | molecular evolution COP-α and -β subunits (2–4) (as detailed later). For brevity, we will henceforth refer to these proteins as the αβ-IFT subunits. he eukaryotic cilium or flagellum is a structure protruding The second group (Fig. 1A, yellow) comprises TTC21, IFT88, Tfrom the cell into the environment. The cilium provides mo- TTC26, TTC30A/B, BBS4, and BBS8, whose domain structure tility by a controlled whip-like or rotational beating. Construction resembles the COP-e subunit and are henceforth referred to as and maintenance of the cilium, together with additional signaling e-IFT subunits. The third group (Fig. 1A, red) comprises the functions, depend on the process of intraflagellar transport (IFT). small GTPases IFT22, IFT27, and BBS3. Finally, the fourth IFT provides active, bidirectional transport of proteins and other group (Fig. 1A, green) comprises BBS1, BBS2, BBS7, and BBS9, molecules along the length of the cilium, delivering structural and represents four homologous subunits in the BBSome. The components and other factors in the organelle. IFT dysfunction remaining IFT subunits (Fig. 1A, white) do not share any detect- results in the inability of the cilium to maintain a normal structure able sequence relationships with each other, or with any other and failure of signaling and sensory pathways, causing complex proteins. Hence, as they do not contain any phylogenetic infor- system-wide disorders and syndromes (1). mation on the origin of the IFT complex, they will not be further IFT is mediated by a large cohort of evolutionarily conserved discussed. Interestingly, members of the four homologous groups subunits, which can be grouped by biochemical and genetic cri- teria into three subcomplexes: IFT-A, IFT-B, and BBSome. Broadly, mutations in any subunit of each of these complexes Author contributions: T.J.P.v.D., M.C.F., and M.A.H. designed research; T.J.P.v.D., M.J.T., M.T., and A. Schlessinger performed research; T.J.P.v.D., M.J.T., M.T., A. Schlessinger, phenocopy each other, indicating close cooperativity and a re- A. Sali, and M.C.F. analyzed data; and T.J.P.v.D., M.T., A. Schlessinger, A. Sali, M.C.F., quirement for complete holocomplexes for functional IFT. Sig- and M.A.H. wrote the paper. nificantly, six IFT complex subunits (WDR19, WDR35, IFT140, The authors declare no conflict of interest. IFT122, IFT172, and IFT80) have predicted secondary structure This article is a PNAS Direct Submission. elements and folds similar to those present in multiple subunits Freely available online through the PNAS open access option. of vesicle coat complexes and the nuclear pore complex (NPC) 1Present address: Gene Center and Center for Integrated Protein Science Munich and (2–4). Their N-terminal region contains WD40 repeats, likely Department of Biochemistry, University of Munich, 81377 Munich, Germany. β forming two -propeller folds, whereas their C-terminal region 2Present address: Department of Pharmacology and Systems Therapeutics and Tisch contains tetratricopeptide repeats (TPR), likely forming an Cancer Institute, Mount Sinai School of Medicine, New York, NY 10029. α-solenoid–like fold. 3M.C.F. and M.A.H. contributed equally to this work. The IFT system has been shown to be homologous to the 4To whom correspondence should be addressed. E-mail: [email protected]. protocoatomer family of complexes, which includes coat protein This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. complex (COP) I, COPII, clathrin/adaptin complex, and the 1073/pnas.1221011110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1221011110 PNAS Early Edition | 1of6 Downloaded by guest on September 27, 2021 IFT-A ABWDR C TTC26 IFT precursor 35 IFT WDR IFT-B c 100 19 IFT 122 140 IFT IFT 74 TTC30 IFT IFT 43 TTC 21 IFT 172 IFT 54 IFT b 100 IFT88 80 IFT 52 25 CLUAP1 e 58 IFT 20 IFT IFT 88 IFT 81 IFT 27 TTC21 57 IFT 46 d TTC 78 22 a 26 TTC BBS8 30 f 97 BBS BBS4 COP-ε BBSome Fig. 1. Phylogenetic analyses of the e-IFT subunits and IFT complex composition. (A) Composition of the IFT subcomplexes. Blue, αβ-IFT subunits with domain structures similar to COPI-α and -β′; yellow, e-IFT subunits with domain structures similar to COPI-e; red, small GTPases; green, putative β-propeller BBS subunits; white, subunits that are not homologous to other subunits. Positions of the subunits do not reflect their actual positions within the IFT complex. (B) Phylogenetic tree of e-IFT subunits. (C) Evolutionary scenario for the origin of IFT-A, IFT-B, and BBSome subcomplexes, based on B. are not confined to a specific subcomplex, indicating a convoluted was IFT-B–like (the IFT-B subunits can be found in both clades origin of the three subcomplexes. Here we discuss two of these originating in node b, whereas the BBSome and IFT-A subunits groups, the αβ-IFT and e-IFT subunits, and report an evolutionary emerge later). BBSome subunits BBS4 and BBS8 originate from reconstruction of their origin. Discussions of the other two groups a duplication at node d followed by a duplication in node f, sug- are provided in SI Discussion. gesting that the BBSome subcomplex emerged later in the proto- IFT complex. Duplication of the ancestral e-IFT subunit at node e α β′ e Common Descent of IFT and COPI- ,- , and - Subunits. Sensitive gave rise to IFT88 (IFT-B) and TTC21 (IFT-A), suggesting that sequence similarity searches [i.e., hidden Markov models (HMMs) the IFT-A subcomplex is the latest addition to the proto-IFT αβ and PSI-BLAST] using the sequences of -IFT subunits (Fig. 1A, complex and completes the extant IFT system. Fig. 1C shows a blue) as queries retrieved many TPR- and WD40-containing α β′ cartoon representation of the sequence of subcomplex emergence. protein sequences, including the and subunits of the COPI The αβ-IFT phylogenetic tree is not fully resolved and sup- complex. However, none of these were retrieved consistently ports two distinct evolutionary scenarios with respect to the or- for all αβ-IFT subunits. This lack of consistency in detection of αβ der in which the subcomplexes originated (SI Discussion provides proteins that are most similar to the -IFT subunits argues more details), one of which is congruent with the scenario for the for a phylogenetic approach to identify the origin of the αβ-IFT e-IFT subunits.
Recommended publications
  • Near-Atomic Structures of the Bbsome Reveal the Basis for Bbsome
    RESEARCH ARTICLE Near-atomic structures of the BBSome reveal the basis for BBSome activation and binding to GPCR cargoes Shuang Yang1†, Kriti Bahl2†, Hui-Ting Chou1‡, Jonathan Woodsmith3, Ulrich Stelzl3, Thomas Walz1*, Maxence V Nachury2* 1Laboratory of Molecular Electron Microscopy, The Rockefeller University, New York, United States; 2Department of Ophthalmology, University of California San Francisco, San Francisco, United States; 3Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz and BioTechMed-Graz, Graz, Austria Abstract Dynamic trafficking of G protein-coupled receptors (GPCRs) out of cilia is mediated by the BBSome. In concert with its membrane recruitment factor, the small GTPase ARL6/BBS3, the BBSome ferries GPCRs across the transition zone, a diffusion barrier at the base of cilia. Here, we present the near-atomic structures of the BBSome by itself and in complex with ARL6GTP, and we describe the changes in BBSome conformation induced by ARL6GTP binding. Modeling the *For correspondence: interactions of the BBSome with membranes and the GPCR Smoothened (SMO) reveals that SMO, [email protected] (TW); and likely also other GPCR cargoes, must release their amphipathic helix 8 from the membrane to [email protected] (MVN) be recognized by the BBSome. †These authors contributed equally to this work Present address: ‡Department of Therapeutic Discovery, Amgen Introduction Inc, South San Francisco, United Cilia dynamically concentrate signaling receptors to sense and transduce signals as varied as light, States odorant molecules, Hedgehog morphogens and ligands of G protein-coupled receptors (GPCRs) Competing interests: The (Anvarian et al., 2019; Bangs and Anderson, 2017; Nachury and Mick, 2019). Highlighting the authors declare that no functional importance of dynamic ciliary trafficking, the appropriate transduction of Hedgehog signal competing interests exist.
    [Show full text]
  • Ciliopathiesneuromuscularciliopathies Disorders Disorders Ciliopathiesciliopathies
    NeuromuscularCiliopathiesNeuromuscularCiliopathies Disorders Disorders CiliopathiesCiliopathies AboutAbout EGL EGL Genet Geneticsics EGLEGL Genetics Genetics specializes specializes in ingenetic genetic diagnostic diagnostic testing, testing, with with ne nearlyarly 50 50 years years of of clinical clinical experience experience and and board-certified board-certified labor laboratoryatory directorsdirectors and and genetic genetic counselors counselors reporting reporting out out cases. cases. EGL EGL Genet Geneticsics offers offers a combineda combined 1000 1000 molecular molecular genetics, genetics, biochemical biochemical genetics,genetics, and and cytogenetics cytogenetics tests tests under under one one roof roof and and custom custom test testinging for for all all medically medically relevant relevant genes, genes, for for domestic domestic andand international international clients. clients. EquallyEqually important important to to improving improving patient patient care care through through quality quality genetic genetic testing testing is is the the contribution contribution EGL EGL Genetics Genetics makes makes back back to to thethe scientific scientific and and medical medical communities. communities. EGL EGL Genetics Genetics is is one one of of only only a afew few clinical clinical diagnostic diagnostic laboratories laboratories to to openly openly share share data data withwith the the NCBI NCBI freely freely available available public public database database ClinVar ClinVar (>35,000 (>35,000 variants variants on on >1700 >1700 genes) genes) and and is isalso also the the only only laboratory laboratory with with a a frefree oen olinnlein dea dtabtaabsaes (eE m(EVmCVlaCslas)s,s f)e, afetuatruinrgin ag vaa vraiarniatn ctl acslasisfiscifiactiaotino sne saercahrc ahn adn rde rpeoprot rrte rqeuqeuset sint tinetrefarcfaec, ew, hwichhic fha cfailcitialiteatse rsa praidp id interactiveinteractive curation curation and and reporting reporting of of variants.
    [Show full text]
  • Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity Received: 11 November 2016 Audrey E
    www.nature.com/scientificreports OPEN Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity Received: 11 November 2016 Audrey E. Hendricks1,2, Elena G. Bochukova3,4, Gaëlle Marenne1, Julia M. Keogh3, Neli Accepted: 10 April 2017 Atanassova3, Rebecca Bounds3, Eleanor Wheeler1, Vanisha Mistry3, Elana Henning3, Published: xx xx xxxx Understanding Society Scientific Group*, Antje Körner5,6, Dawn Muddyman1, Shane McCarthy1, Anke Hinney7, Johannes Hebebrand7, Robert A. Scott8, Claudia Langenberg8, Nick J. Wareham8, Praveen Surendran9, Joanna M. Howson9, Adam S. Butterworth9,10, John Danesh1,9,10, EPIC-CVD Consortium*, Børge G Nordestgaard11,12, Sune F Nielsen11,12, Shoaib Afzal11,12, SofiaPa padia3, SofieAshford 3, Sumedha Garg3, Glenn L. Millhauser13, Rafael I. Palomino13, Alexandra Kwasniewska3, Ioanna Tachmazidou1, Stephen O’Rahilly3, Eleftheria Zeggini1, UK10K Consortium*, Inês Barroso1,3 & I. Sadaf Farooqi3 Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants inBBS1 , BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10−3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes.
    [Show full text]
  • Ciliopathies Gene Panel
    Ciliopathies Gene Panel Contact details Introduction Regional Genetics Service The ciliopathies are a heterogeneous group of conditions with considerable phenotypic overlap. Levels 4-6, Barclay House These inherited diseases are caused by defects in cilia; hair-like projections present on most 37 Queen Square cells, with roles in key human developmental processes via their motility and signalling functions. Ciliopathies are often lethal and multiple organ systems are affected. Ciliopathies are London, WC1N 3BH united in being genetically heterogeneous conditions and the different subtypes can share T +44 (0) 20 7762 6888 many clinical features, predominantly cystic kidney disease, but also retinal, respiratory, F +44 (0) 20 7813 8578 skeletal, hepatic and neurological defects in addition to metabolic defects, laterality defects and polydactyly. Their clinical variability can make ciliopathies hard to recognise, reflecting the ubiquity of cilia. Gene panels currently offer the best solution to tackling analysis of genetically Samples required heterogeneous conditions such as the ciliopathies. Ciliopathies affect approximately 1:2,000 5ml venous blood in plastic EDTA births. bottles (>1ml from neonates) Ciliopathies are generally inherited in an autosomal recessive manner, with some autosomal Prenatal testing must be arranged dominant and X-linked exceptions. in advance, through a Clinical Genetics department if possible. Referrals Amniotic fluid or CV samples Patients presenting with a ciliopathy; due to the phenotypic variability this could be a diverse set should be sent to Cytogenetics for of features. For guidance contact the laboratory or Dr Hannah Mitchison dissecting and culturing, with ([email protected]) / Prof Phil Beales ([email protected]) instructions to forward the sample to the Regional Molecular Genetics Referrals will be accepted from clinical geneticists and consultants in nephrology, metabolic, laboratory for analysis respiratory and retinal diseases.
    [Show full text]
  • BBS1 Is Involved in Retrograde Trafficking of Ciliary Gpcrs in the Context of the Bbsome Complex
    RESEARCH ARTICLE BBS1 is involved in retrograde trafficking of ciliary GPCRs in the context of the BBSome complex Shohei Nozaki☯, Yohei Katoh☯, Takuya Kobayashi, Kazuhisa Nakayama* Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan ☯ These authors contributed equally to this work. * [email protected] a1111111111 a1111111111 a1111111111 a1111111111 Abstract a1111111111 Protein trafficking within cilia is mediated by the intraflagellar transport (IFT) machinery com- posed of large protein complexes. The BBSome consists of eight BBS proteins encoded by causative genes of Bardet-Biedl syndrome (BBS), and has been implicated in the trafficking of ciliary membrane proteins, including G protein-coupled receptors (GPCRs), by connect- OPEN ACCESS ing the IFT machinery to cargo GPCRs. Membrane recruitment of the BBSome to promote Citation: Nozaki S, Katoh Y, Kobayashi T, cargo trafficking has been proposed to be regulated by the Arf-like small GTPase ARL6/ Nakayama K (2018) BBS1 is involved in retrograde trafficking of ciliary GPCRs in the context of the BBS3, through its interaction with the BBS1 subunit of the BBSome. We here investigated BBSome complex. PLoS ONE 13(3): e0195005. how the BBSome core subcomplex composed of BBS1, BBS2, BBS7, and BBS9 assem- https://doi.org/10.1371/journal.pone.0195005 bles and interacts with ARL6, and found that the ARL6±BBS1 interaction is reinforced by Editor: Hemant Khanna, University of BBS9. BBS1-knockout (KO) cells showed defects in the ciliary entry of other BBSome sub- Massachusetts Medical School, UNITED STATES units and ARL6, and in ciliary retrograde trafficking and the export of the GPCRs, Smooth- Received: December 4, 2017 ened and GPR161.
    [Show full text]
  • Myopia in African Americans Is Significantly Linked to Chromosome 7P15.2-14.2
    Genetics Myopia in African Americans Is Significantly Linked to Chromosome 7p15.2-14.2 Claire L. Simpson,1,2,* Anthony M. Musolf,2,* Roberto Y. Cordero,1 Jennifer B. Cordero,1 Laura Portas,2 Federico Murgia,2 Deyana D. Lewis,2 Candace D. Middlebrooks,2 Elise B. Ciner,3 Joan E. Bailey-Wilson,1,† and Dwight Stambolian4,† 1Department of Genetics, Genomics and Informatics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States 2Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States 3The Pennsylvania College of Optometry at Salus University, Elkins Park, Pennsylvania, United States 4Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States Correspondence: Joan E. PURPOSE. The purpose of this study was to perform genetic linkage analysis and associ- Bailey-Wilson, NIH/NHGRI, 333 ation analysis on exome genotyping from highly aggregated African American families Cassell Drive, Suite 1200, Baltimore, with nonpathogenic myopia. African Americans are a particularly understudied popula- MD 21131, USA; tion with respect to myopia. [email protected]. METHODS. One hundred six African American families from the Philadelphia area with a CLS and AMM contributed equally to family history of myopia were genotyped using an Illumina ExomePlus array and merged this work and should be considered co-first authors. with previous microsatellite data. Myopia was initially measured in mean spherical equiv- JEB-W and DS contributed equally alent (MSE) and converted to a binary phenotype where individuals were identified as to this work and should be affected, unaffected, or unknown.
    [Show full text]
  • Nonsyndromic Craniosynostosis
    Nonsyndromic craniosynostosis: novel coding variants Anshuman Sewda, Sierra White, Monica Erazo, Ke Hao, Gemma García-Fructuoso, Ivette Fernández-Rodriguez, Yann Heuzé, Joan Richtsmeier, Paul Romitti, Boris Reva, et al. To cite this version: Anshuman Sewda, Sierra White, Monica Erazo, Ke Hao, Gemma García-Fructuoso, et al.. Nonsyn- dromic craniosynostosis: novel coding variants. Pediatric Research, Nature Publishing Group, 2019, 85 (4), pp.463-468. 10.1038/s41390-019-0274-2. hal-02322180 HAL Id: hal-02322180 https://hal.archives-ouvertes.fr/hal-02322180 Submitted on 11 Jan 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Pediatr Manuscript Author Res. Author manuscript; Manuscript Author available in PMC 2019 July 14. Published in final edited form as: Pediatr Res. 2019 March ; 85(4): 463–468. doi:10.1038/s41390-019-0274-2. Nonsyndromic Craniosynostosis: Novel Coding Variants Anshuman Sewda1,*, Sierra R. White1, Monica Erazo1, Ke Hao1, Gemma García-Fructuoso2, Ivette
    [Show full text]
  • BBS6, BBS10, and BBS12 Form a Complex with CCT/Tric Family Chaperonins and Mediate Bbsome Assembly
    BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly Seongjin Seoa,c, Lisa M. Bayeb, Nathan P. Schulza,c, John S. Becka,c, Qihong Zhanga,c, Diane C. Slusarskib, and Val C. Sheffielda,c,1 aDepartment of Pediatrics, bDepartment of Biology, and cHoward Hughes Medical Institute, University of Iowa, Iowa City, IA 52242 Edited by Kathryn V. Anderson, Sloan-Kettering Institute, New York, NY, and approved November 25, 2009 (received for review September 9, 2009) Bardet-Biedl syndrome (BBS) is a human genetic disorder resulting one component of the BBSome, BBS1, directly interacts with the in obesity, retinal degeneration, polydactyly, and nephropathy. leptin receptor and that leptin signaling is attenuated in BBS Recent studies indicate that trafficking defects to the ciliary mem- gene knockout mice, implicating BBS function in a broad range brane are involved in this syndrome. Here, we show that a novel of membrane receptor signaling (33). complex composed of three chaperonin-like BBS proteins (BBS6, Three of the remaining BBS proteins (BBS6, BBS10, and BBS10, and BBS12) and CCT/TRiC family chaperonins mediates BBS12) have sequence homology to the CCT (also known as BBSome assembly, which transports vesicles to the cilia. Chaperonin- TRiC) family of group II chaperonins (17, 24, 25). CCT proteins like BBS proteins interact with a subset of BBSome subunits and form an ≈900 kDa hetero-oligomeric complex that mediates promote their association with CCT chaperonins. CCT activity is protein folding in an ATP-dependent manner (34, 35). The CCT essential for BBSome assembly, and knockdown of CCT chaperonins complex consists of two stacked rings, each of which is composed in zebrafish results in BBS phenotypes.
    [Show full text]
  • Whole-Exome Sequencing Identifies Causative Mutations in Families
    BASIC RESEARCH www.jasn.org Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract Amelie T. van der Ven,1 Dervla M. Connaughton,1 Hadas Ityel,1 Nina Mann,1 Makiko Nakayama,1 Jing Chen,1 Asaf Vivante,1 Daw-yang Hwang,1 Julian Schulz,1 Daniela A. Braun,1 Johanna Magdalena Schmidt,1 David Schapiro,1 Ronen Schneider,1 Jillian K. Warejko,1 Ankana Daga,1 Amar J. Majmundar,1 Weizhen Tan,1 Tilman Jobst-Schwan,1 Tobias Hermle,1 Eugen Widmeier,1 Shazia Ashraf,1 Ali Amar,1 Charlotte A. Hoogstraaten,1 Hannah Hugo,1 Thomas M. Kitzler,1 Franziska Kause,1 Caroline M. Kolvenbach,1 Rufeng Dai,1 Leslie Spaneas,1 Kassaundra Amann,1 Deborah R. Stein,1 Michelle A. Baum,1 Michael J.G. Somers,1 Nancy M. Rodig,1 Michael A. Ferguson,1 Avram Z. Traum,1 Ghaleb H. Daouk,1 Radovan Bogdanovic,2 Natasa Stajic,2 Neveen A. Soliman,3,4 Jameela A. Kari,5,6 Sherif El Desoky,5,6 Hanan M. Fathy,7 Danko Milosevic,8 Muna Al-Saffar,1,9 Hazem S. Awad,10 Loai A. Eid,10 Aravind Selvin,11 Prabha Senguttuvan,12 Simone Sanna-Cherchi,13 Heidi L. Rehm,14 Daniel G. MacArthur,14,15 Monkol Lek,14,15 Kristen M. Laricchia,15 Michael W. Wilson,15 Shrikant M. Mane,16 Richard P. Lifton,16,17 Richard S. Lee,18 Stuart B. Bauer,18 Weining Lu,19 Heiko M. Reutter ,20,21 Velibor Tasic,22 Shirlee Shril,1 and Friedhelm Hildebrandt1 Due to the number of contributing authors, the affiliations are listed at the end of this article.
    [Show full text]
  • BBS6, BBS10, and BBS12 Form a Complex with CCT/Tric Family Chaperonins and Mediate Bbsome Assembly
    BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly Seongjin Seoa,c, Lisa M. Bayeb, Nathan P. Schulza,c, John S. Becka,c, Qihong Zhanga,c, Diane C. Slusarskib, and Val C. Sheffielda,c,1 aDepartment of Pediatrics, bDepartment of Biology, and cHoward Hughes Medical Institute, University of Iowa, Iowa City, IA 52242 Edited by Kathryn V. Anderson, Sloan-Kettering Institute, New York, NY, and approved November 25, 2009 (received for review September 9, 2009) Bardet-Biedl syndrome (BBS) is a human genetic disorder resulting one component of the BBSome, BBS1, directly interacts with the in obesity, retinal degeneration, polydactyly, and nephropathy. leptin receptor and that leptin signaling is attenuated in BBS Recent studies indicate that trafficking defects to the ciliary mem- gene knockout mice, implicating BBS function in a broad range brane are involved in this syndrome. Here, we show that a novel of membrane receptor signaling (33). complex composed of three chaperonin-like BBS proteins (BBS6, Three of the remaining BBS proteins (BBS6, BBS10, and BBS10, and BBS12) and CCT/TRiC family chaperonins mediates BBS12) have sequence homology to the CCT (also known as BBSome assembly, which transports vesicles to the cilia. Chaperonin- TRiC) family of group II chaperonins (17, 24, 25). CCT proteins like BBS proteins interact with a subset of BBSome subunits and form an ≈900 kDa hetero-oligomeric complex that mediates promote their association with CCT chaperonins. CCT activity is protein folding in an ATP-dependent manner (34, 35). The CCT essential for BBSome assembly, and knockdown of CCT chaperonins complex consists of two stacked rings, each of which is composed in zebrafish results in BBS phenotypes.
    [Show full text]
  • Ciliary Genes in Renal Cystic Diseases
    cells Review Ciliary Genes in Renal Cystic Diseases Anna Adamiok-Ostrowska * and Agnieszka Piekiełko-Witkowska * Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland * Correspondence: [email protected] (A.A.-O.); [email protected] (A.P.-W.); Tel.: +48-22-569-3810 (A.P.-W.) Received: 3 March 2020; Accepted: 5 April 2020; Published: 8 April 2020 Abstract: Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer.
    [Show full text]
  • Identification of a Novel Homozygous Missense (C. 443A> T: P. N148I) Mutation in BBS2 in a Kashmiri Family with Bardet-Biedl Syndrome
    Hindawi BioMed Research International Volume 2021, Article ID 6626015, 9 pages https://doi.org/10.1155/2021/6626015 Research Article Identification of a Novel Homozygous Missense (c.443A>T:p.N148I) Mutation in BBS2 in a Kashmiri Family with Bardet-Biedl Syndrome Ghazanfar Ali ,1 Sadia ,1 Jia Nee Foo,2,3 Abdul Nasir ,4 Chu-Hua Chang,2,3 Elaine GuoYan Chew,2,3 Zahid Latif ,5 Zahid Azeem,6 Syeda Ain-ul-Batool ,1 Syed Akif Raza Kazmi ,7 Naheed Bashir Awan,1 Abdul Hameed Khan ,1 Fazal-Ur- Rehman ,8 Madiha Khalid ,1,9 Abdul Wali ,10 Samina Sarwar ,5 Wasim Akhtar,11 Ansar Ahmed Abbasi,12 and Rameez Nisar12 1Department of Biotechnology, University of Azad Jammu and Kashmir, P.O. Box 13100, Muzaffarabad, Pakistan 2Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232 3Human Genetics, Genome Institute of Singapore, A∗STAR, 60 Biopolis Street, Singapore 138672 4Molecular Science and Technology, Ajou University, Suwon, Republic of Korea 5Department of Zoology, University of Azad Jammu and Kashmir, P.O. Box 13100, Muzaffarabad, Pakistan 6Department of Biochemistry/Molecular Biology AJK Medical College, Muzaffarabad, Pakistan 7Department of Chemistry Government College University Lahore, Pakistan 8Department of Microbiology, Faculty of Life Sciences, University of Balochistan, Quetta, Pakistan 9Department of Biotechnology, Women University of Azad Kashmir Bagh, 12500, Pakistan 10Department of Biotechnology, Faculty of Life Sciences and Informatics, BUITEMS, 87100 Quetta, Pakistan 11Department of Botany, University of Azad Jammu and Kashmir, Muzaffarabad, Pakistan 12Department of Zoology, Mirpur University of Science and Technology (MUST), Mirpur AJK, Pakistan Correspondence should be addressed to Ghazanfar Ali; [email protected] Received 3 October 2020; Revised 31 December 2020; Accepted 31 January 2021; Published 23 February 2021 Academic Editor: Sercan Erg n Copyright © 2021 Ghazanfar Ali et al.
    [Show full text]