Structural basis for membrane targeting of the BBSome by ARL6.

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.

• Authors: André Mourão, Andrew R Nager, Maxence V Nachury, Esben Lorentzen
• Journal: Nature structural & molecular biology (Nat Struct Mol Biol) Vol. 21 Issue 12 Pg. 1035-41 (Dec 2014) ISSN: 1545-9985 [Electronic] United States
• PMID: 25402481 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bbs1 protein, human
• Microtubule-Associated Proteins
• Plant Proteins
• Recombinant Proteins
• Guanosine Triphosphate
• ARL6 protein, human
• ADP-Ribosylation Factors

Topics

• ADP-Ribosylation Factors (chemistry, genetics, metabolism)
• Bardet-Biedl Syndrome (genetics)
• Chlamydomonas reinhardtii (chemistry, genetics, metabolism)
• Cilia (metabolism)
• Crystallography, X-Ray
• Guanosine Triphosphate (metabolism)
• Humans
• Microtubule-Associated Proteins (chemistry, genetics, metabolism)
• Models, Molecular
• Plant Proteins (chemistry, genetics, metabolism)
• Point Mutation
• Protein Conformation
• Protein Transport
• Recombinant Proteins (chemistry, genetics, metabolism)