Near-atomic structures of the BBSome reveal the basis for BBSome activation and binding to GPCR cargoes

Elife. 2020 Jun 8:9:e55954. doi: 10.7554/eLife.55954.

Abstract

Dynamic trafficking of G protein-coupled receptors (GPCRs) out of cilia is mediated by the BBSome. In concert with its membrane recruitment factor, the small GTPase ARL6/BBS3, the BBSome ferries GPCRs across the transition zone, a diffusion barrier at the base of cilia. Here, we present the near-atomic structures of the BBSome by itself and in complex with ARL6GTP, and we describe the changes in BBSome conformation induced by ARL6GTP binding. Modeling the interactions of the BBSome with membranes and the GPCR Smoothened (SMO) reveals that SMO, and likely also other GPCR cargoes, must release their amphipathic helix 8 from the membrane to be recognized by the BBSome.

Keywords: BBSome; Bardet-Biedl Syndrome; Cilia; GPCR; cell biology; hedgehog signaling; molecular biophysics; mouse; smoothened; structural biology.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cattle
  • Cryoelectron Microscopy
  • Gene Expression Regulation
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Domains
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Recombinant Proteins

Substances

  • Carrier Proteins
  • Receptors, G-Protein-Coupled
  • Recombinant Proteins