Structural basis for membrane targeting of the BBSome by ARL6

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

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Associated data

  • PDB/4V0K
  • PDB/4V0L
  • PDB/4V0M
  • PDB/4V0N
  • PDB/4V0O