Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling.
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.
Wiens
Cheryl J
CJ
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
Tong
Yufeng
Y
Esmail
Muneer A
MA
Oh
Edwin
E
Gerdes
Jantje M
JM
Wang
Jihong
J
Tempel
Wolfram
W
Rattner
Jerome B
JB
Katsanis
Nicholas
N
Park
Hee-Won
HW
Leroux
Michel R
MR
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*
D051153:Wnt Proteins; C491435:ARL6 protein, human; D020727:ADP-Ribosylation Factors