title: Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling.
abstract: The expansive family of metazoan ADP-ribosylation factor and ADP-ribosylation factor-like small GTPases is known to play essential roles in modulating membrane trafficking and cytoskeletal functions. Here, we present the crystal structure of ARL6, mutations in which cause Bardet-Biedl syndrome (BBS3), and reveal its unique ring-like localization at the distal end of basal bodies, in proximity to the so-called ciliary gate where vesicles carrying ciliary cargo fuse with the membrane. Overproduction of GDP- or GTP-locked variants of ARL6/BBS3 in vivo influences primary cilium length and abundance. ARL6/BBS3 also modulates Wnt signaling, a signal transduction pathway whose association with cilia in vertebrates is just emerging. Importantly, this signaling function is lost in ARL6 variants containing BBS-associated point mutations. By determining the structure of GTP-bound ARL6/BBS3, coupled with functional assays, we provide a mechanistic explanation for such pathogenic alterations, namely altered nucleotide binding. Our findings therefore establish a previously unknown role for ARL6/BBS3 in mammalian ciliary (dis)assembly and Wnt signaling and provide the first structural information for a BBS protein.
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Cheryl J
authors.initials: CJ
authors.lastname: Wiens
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Tong
authors.forename: Muneer A
authors.initials: MA
authors.lastname: Esmail
authors.forename: Edwin
authors.initials: E
authors.lastname: Oh
authors.forename: Jantje M
authors.initials: JM
authors.lastname: Gerdes
authors.forename: Jihong
authors.initials: J
authors.lastname: Wang
authors.forename: Wolfram
authors.initials: W
authors.lastname: Tempel
authors.forename: Jerome B
authors.initials: JB
authors.lastname: Rattner
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Hee-Won
authors.initials: HW
authors.lastname: Park
authors.forename: Michel R
authors.initials: MR
authors.lastname: Leroux
mesh_terms: D020727:ADP-Ribosylation Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020788:Bardet-Biedl Syndrome / Q000201:enzymology* / Q000235:genetics; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology / Q000235:genetics; D002923:Cilia / Q000201:enzymology / Q000235:genetics; D018360:Crystallography, X-Ray; D003599:Cytoskeleton / Q000201:enzymology / Q000235:genetics; D006801:Humans; D017354:Point Mutation; D015398:Signal Transduction; D051153:Wnt Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins; C491435:ARL6 protein, human; D020727:ADP-Ribosylation Factors