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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 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- mation on the origin of the IFT complex, they will not be further system-wide disorders and syndromes (1). EVOLUTION 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 | April 23, 2013 | vol. 110 | no. 17 | 6943–6948 Downloaded by guest on October 1, 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.
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