Structural basis for membrane targeting of the BBSome by ARL6.
The BBSome is a coat-like ciliary trafficking complex composed of proteins mutated in Bardet-Biedl syndrome (BBS). A critical step in BBSome-mediated sorting is recruitment of the BBSome to membranes by the GTP-bound Arf-like GTPase ARL6. We have determined crystal structures of Chlamydomonas reinhardtii ARL6-GDP, ARL6-GTP and the ARL6-GTP-BBS1 complex. The structures demonstrate how ARL6-GTP binds the BBS1 β-propeller at blades 1 and 7 and explain why GTP- but not GDP-bound ARL6 can recruit the BBSome to membranes. Single point mutations in the ARL6-GTP-BBS1 interface abolish the interaction of ARL6 with the BBSome and prevent the import of BBSomes into cilia. Furthermore, we show that BBS1 with the M390R mutation, responsible for 30% of all reported BBS disease cases, fails to interact with ARL6-GTP, thus providing a molecular rationale for patient pathologies.
Department of Structural Cell Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
André
A
Mourão
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA.
Andrew R
AR
Nager
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA.
Maxence V
0000000349181562
MV
Nachury
Department of Structural Cell Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
Esben
E
Lorentzen
D020727:ADP-Ribosylation Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020788:Bardet-Biedl Syndrome / Q000235:genetics; D016825:Chlamydomonas reinhardtii / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002923:Cilia / Q000378:metabolism; D018360:Crystallography, X-Ray; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D010940:Plant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D011487:Protein Conformation; D021381:Protein Transport; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
C464790:Bbs1 protein, human; D008869:Microtubule-Associated Proteins; D010940:Plant Proteins; D011994:Recombinant Proteins; D006160:Guanosine Triphosphate; C491435:ARL6 protein, human; D020727:ADP-Ribosylation Factors