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Nat Struct Mol Biol. 2014 Dec;21(12):1035-41. doi: 10.1038/nsmb.2920. Epub 2014 Nov 17.

Structural basis for membrane targeting of the BBSome by ARL6.

Author information

1
Department of Structural Cell Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
2
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA.

Abstract

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.

PMID:
25402481
PMCID:
PMC4255524
DOI:
10.1038/nsmb.2920
[Indexed for MEDLINE]
Free PMC Article

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