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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ADP-Ribosylation Factors / chemistry
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ADP-Ribosylation Factors / genetics
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ADP-Ribosylation Factors / metabolism*
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Bardet-Biedl Syndrome / genetics
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Chlamydomonas reinhardtii / chemistry
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Chlamydomonas reinhardtii / genetics
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Chlamydomonas reinhardtii / metabolism*
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Cilia / metabolism
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Crystallography, X-Ray
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Guanosine Triphosphate / metabolism
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Humans
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Microtubule-Associated Proteins / chemistry
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism*
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Models, Molecular
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Plant Proteins / chemistry
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Plant Proteins / genetics
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Plant Proteins / metabolism*
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Point Mutation
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Protein Conformation
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Protein Transport
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
Substances
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Bbs1 protein, human
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Microtubule-Associated Proteins
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Plant Proteins
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Recombinant Proteins
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Guanosine Triphosphate
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ARL6 protein, human
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ADP-Ribosylation Factors
Associated data
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PDB/4V0K
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PDB/4V0L
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PDB/4V0M
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PDB/4V0N
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PDB/4V0O