Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 21, Issue 12, Pages 1035-1041Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2920
Keywords
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Funding
- Emmy Noether grant (Deutsche Forschungsgemeinschaft) [LO1627/1-1]
- European Research Council [310343]
- European Molecular Biology Organization Young Investigator program
- Fayez Sarofim Fellowship of the Damon Runyon Cancer Research Foundation [DRG 2160-13]
- NIH/National Institute of General Medical Sciences [R01GM089933]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM089933] Funding Source: NIH RePORTER
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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 beta-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.
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