RT Journal Article
SR Electronic
T1 Near-atomic structures of the BBSome reveal a novel mechanism for transition zone crossing
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.29.925610
DO 10.1101/2020.01.29.925610
A1 Kriti Bahl
A1 Shuang Yang
A1 Hui-Ting Chou
A1 Jonathan Woodsmith
A1 Ulrich Stelzl
A1 Thomas Walz
A1 Maxence V. Nachury
YR 2020
UL http://biorxiv.org/content/early/2020/01/30/2020.01.29.925610.abstract
AB The BBSome is a complex of eight Bardet-Biedl Syndrome (BBS) proteins that removes signaling receptors from cilia. The GTPase ARL6/BBS3 recruits the BBSome to the ciliary membrane where the BBSome–ARL6GTP complex ferries G protein-coupled receptors (GPCRs) across the transition zone, a diffusion barrier at the base of cilia. Here, we find that the BBSome undergoes a conformational change upon recruitment to membranes by ARL6GTP. Modeling the binding of the BBSome to membranes and to the GPCR Smoothened (SMO) reveals that the amphipathic helix 8 of SMO must be released from the membrane for SMO to be recognized by the BBSome. Underscoring the functional importance of amphipathic helix extraction in TZ crossing, we find that exchanging the amphipathic helix of ARL6 for one that embeds deeper into the membrane blocks BBSome-mediated exit of GPCRs from cilia. We propose that the rigid curvature and dense lipid packing of the transition zone reject asymmetric insertions in the inner leaflet and that the BBSome licenses transition zone crossing by extracting bulky amphipathic helices from the inner leaflet.