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Intraflagellar Transport Complex Structure and Cargo Interactions Sagar Bhogaraju1, Benjamin D Engel2 and Esben Lorentzen1*

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Intraflagellar Transport Complex Structure and Cargo Interactions Sagar Bhogaraju1, Benjamin D Engel2 and Esben Lorentzen1* Bhogaraju et al. Cilia ,:2013, 2:10 http://www.ciliajournal.com/content/2/1/10http://www.ciliajournal.com/content/// REVIEW Open Access Intraflagellar transport complex structure and cargo interactions Sagar Bhogaraju1, Benjamin D Engel2 and Esben Lorentzen1* Abstract Intraflagellar transport (IFT) is required for the assembly and maintenance of cilia, as well as the proper function of ciliary motility and signaling. IFT is powered by molecular motors that move along the axonemal microtubules, carrying large complexes of IFT proteins that travel together as so-called trains. IFT complexes likely function as adaptors that mediate interactions between anterograde/retrograde motors and ciliary cargoes, facilitating cargo transport between the base and tip of the cilium. Here, we provide an up-to-date review of IFT complex structure and architecture, and discuss how interactions with cargoes and motors may be achieved. Keywords: Intraflagellar transport, Cilium, IFT, IFT complex, IFT cargo Review Structural investigations of IFT complexes have been Twenty years ago, Kozminsky and colleagues first de- limited so far to electron tomographic reconstructions scribed intraflagellar transport (IFT) as a motility in the of IFT particles in situ [32] and the high-resolution crys- Chlamydomonas flagellum that is distinct from flagellar tal structure of the IFT25/27 sub-complex [33]. How- beating [1]. IFT trains were observed by electron mi- ever, the overall architecture of the IFT complex is croscopy to be linear arrays of electron-dense particles starting to take shape, largely as a result of biochemical spanning the distance between the outer doublet micro- studies [25,26,34,35]. In this review we attempt to partition tubules and the flagellar membrane. Following the dis- IFT proteins into principal domains (PD) and auxiliary do- covery of IFT, biochemical purification of native IFT mains (AD) based on the current literature. Whereas PD complexes from Chlamydomonas revealed 15 polypep- mutations lead to IFT complex destabilization with general tides that organize into two IFT sub-complexes, known ciliogenesis phenotypes, AD mutations may facilitate the as IFT-A and IFT-B [2,3]. IFT polypeptide orthologues study of specific IFT protein functionality. Such a division were also found in mice [4,5], suggesting that IFT pro- may assist in designing experiments to probe the roles of teins are largely conserved. Subsequent studies identified individual IFT proteins in cilium formation and function. additional IFT proteins, bringing the current IFT protein count up to 20 [5-11]. Mutations in IFT proteins have been shown to cause several ciliopathies [12-22]. The The intraflagellar transport complex: a protein-protein genetic deletion of an entire IFT protein often leads to a interaction platform? general defect in cilia assembly (presumably due to IFT Bioinformatic analysis of IFT proteins predicts a large complex disruption), making it difficult to assess the number of potential protein-protein interaction domains β specific functions of individual IFT proteins from mu- such as tetratrico peptide repeats (TPRs), WD40 - tant phenotypes alone [8,23-31]. Thus, a more complete propellers and coiled-coils [36-39]. Strikingly, with the understanding of IFT protein function in ciliogenesis, in- exception of the two small GTPases IFT22 and IFT27, cluding cargo and motor interactions, will require de- none of the other IFT proteins are predicted to have en- tailed molecular and structural studies of IFT complexes. zymatic activity. The prediction is thus that the IFT complex forms a large platform with multiple protein interaction sites that allows binding to molecular motors * Correspondence: [email protected] as well as ciliary cargoes. 1Department of Structural Cell Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany Structure prediction using the HHpred server [40] re- Full list of author information is available at the end of the article vealed that most IFT proteins likely contain multiple © 2013 Bhogaraju et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Bhogaraju et al. Cilia ,:2013, 2:10 Page 2 of 9 http://www.ciliajournal.com/content/2/1/10http://www.ciliajournal.com/content/// domains [39]. Limited proteolysis on in vitro recon- an AD [35]. The peripheral IFT proteins IFT54 and stituted IFT complexes demonstrated that only a subset IFT57 both have predicted coiled-coil domains at the of these domains are required for IFT complex forma- C-termini that interact with IFT20 [43-45]. However, tion, indicating that numerous domains are available to the N-terminal regions of both IFT57 and IFT54 are interact with other binding partners such as ciliary car- predicted to be alpha helical domains that could consti- goes or motors [35]. Most IFT proteins can therefore be tute ADs [39] (Figure 1). divided into PDs and ADs as described above (Figure 1). It is important to note that while the PD/AD boundary The main function of PDs is to provide structural stabi- of some IFT proteins is well defined, this is not the case lity, and thus they are well conserved in protein se- for all IFT proteins. In particular, TPR domain-containing quence to ensure the integrity of IFT complex proteins such as IFT70 and IFT88 may possess a single formation. However, most IFT protein domains not re- structural module that functions as both a PD and an AD quired for IFT complex stability (the ADs) are also (Figure 1). Another example is IFT25 and the small highly conserved in sequence, likely reflecting important GTPase IFT27, which form a stable heterodimer that can functions such as ciliary cargo interactions. A good ex- be considered as a single structural module [33]. While ample of the PD/AD division is IFT46, a core compo- the IFT25/27 heterodimer directly binds the “core” IFT74/ nent of IFT-B, where only the IFT46 C-terminal domain 81 complex [35], it also contains a conserved surface patch is required for the stability of the IFT complex via inter- in close proximity to the GTPase active site of IFT27 that action with the C-terminal domain of IFT52 [25,35], may interact with a yet unidentified binding partner in a while the N-terminal domain is involved in the ciliary nucleotide-state-dependent manner [33]. Interestingly, transport of outer dynein arms (ODAs) [24,41,42]. Simi- IFT25 knockout mice show no ciliogenesis defects but die larly, IFT52 interacts directly with at least four different at birth due to sonic hedgehog (Shh) signaling dysfunction IFT proteins (IFT74/81, IFT46, IFT70 and IFT88) via its [46]. This indicates that the IFT25/27 sub-complex is not middle and C-terminal domains, while the conserved needed for the stability of the IFT complex and may func- N-terminal domain is not required for IFT-B complex tion in the IFT of Shh signaling components. Additionally, formation and thus likely constitutes an AD [25,35]. IFT25 and IFT27 are not present in Caenorhabditis The N-terminal domain of IFT74 is also not required elegans and Drosophila melanogaster [10,38]. Thus, IFT25/ for IFT-B core complex formation and may constitute 27 may be defined as an AD module (Figure 1). IFT-B complex IFT-A complex IFT-B“core” 121 139 22 54N 54C 20 25/27 ? 43 57N 57C 81N 81C ? 74N 74C 52C Transport of 144 46C ODA16 122 46N outer dynein arms TULP3 Transport of ciliary GPCRs ? 52N 52M 70 ? Ttll6 Tubulin polyglutamylation PD/AD 140 OSM-3 Motor docking 1. Folding of ciliary proteins 88 MRJ IFT-A“core” 2. Guanylyl cyclase 1 PD/AD ? transport 80 Auxiliary domain (AD) 172N 172C Principal domain (PD) Unknown IFT complex remodeling Dynein1b at the ciliary tip EB1 ? Figure 1 Domain organization and known cargo interactions of intraflagellar transport complex proteins. Intraflagellar transport (IFT) proteins are divided into distinct modules, referred to in this review as principal domains (PDs) and auxiliary domains (ADs), serving principal structural (blue) and auxiliary interaction (red) roles, respectively. Proteins for which there may not be a clear boundary between PD and AD are labeled as “PD/AD”. The probable interacting cargoes of various IFT ADs are indicated with a dashed line. The ADs of IFT81, IFT74, IFT52, IFT54 and IFT57 still remain to be characterized. All of the IFT proteins are abbreviated as the numerical part of their names. The letters N, M and C next to the numbers refer to the N-terminal, middle and C-terminal domains of the corresponding protein. IFT-A proteins, IFT80 and IFT22 are colored grey because their associations with other IFT proteins and ciliary cargoes are poorly characterized. EB1, End binding protein 1; GPCR, G-protein coupled receptor; MRJ, Mammalian relative of DNAJ; ODA, outer dynein arms; OSM, Osmotic avoidance abnormal protein; Ttll6, Tubulin tyrosine ligase-like 6; TULP3, tubby like protein 3. Bhogaraju et al. Cilia ,:2013, 2:10 Page 3 of 9 http://www.ciliajournal.com/content/2/1/10http://www.ciliajournal.com/content/// Ciliary targeting sequences motif inserted into its third intracellular loop showed Proteins that localize to subcellular compartments such markedly increased ciliary localization [62]. Recently, a as mitochondria or the nucleus have distinct sequence similar signal sequence was found in the third intracellular motifs (known as cellular ZIP codes) that specifically tar- loop of another ciliary GPCR, melanin-concentrating hor- get them to their respective organelles [47]. Although mone receptor 1 [63]. These results indicate that the Ax the cilium is topologically equivalent to the cytoplasm, (S/A)xQ motif is both necessary and sufficient for the there are transition zone structures at the ciliary base localization of these GPCRs.
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