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Structure. 2019 Sep 3;27(9):1384-1394.e4. doi: 10.1016/j.str.2019.06.006. Epub 2019 Jul 11.

The Molecular Architecture of Native BBSome Obtained by an Integrated Structural Approach.

Author information

1
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, CA 94305, USA.
3
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
4
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz and BioTechMed-Graz, Graz, Austria.
5
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
6
Laboratoire de Génétique Médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine FMTS, Université de Strasbourg, 67091 Strasbourg, France; Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France.
7
Laboratoire de Génétique Médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine FMTS, Université de Strasbourg, 67091 Strasbourg, France; Centre de Référence pour les Affections Rares en Génétique Ophtalmologique, CARGO, Filière SENSGENE, Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France.
8
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA. Electronic address: dimaio@u.washington.edu.
9
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, CA 94305, USA; Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: maxence.nachury@ucsf.edu.
10
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Molecular Electron Microscopy, The Rockefeller University, New York, NY 10065, USA. Electronic address: twalz@rockefeller.edu.

Abstract

The unique membrane composition of cilia is maintained by a diffusion barrier at the transition zone that is breached when the BBSome escorts signaling receptors out of cilia. Understanding how the BBSome removes proteins from cilia has been hampered by a lack of structural information. Here, we present a nearly complete Cα model of BBSome purified from cow retina. The model is based on a single-particle cryo-electron microscopy density map at 4.9-Å resolution that was interpreted with the help of comprehensive Rosetta-based structural modeling constrained by crosslinking mass spectrometry data. We find that BBSome subunits have a very high degree of interconnectivity, explaining the obligate nature of the complex. Furthermore, like other coat adaptors, the BBSome exists in an autoinhibited state in solution and must thus undergo a conformational change upon recruitment to membranes by the small GTPase ARL6/BBS3. Our model provides the first detailed view of the machinery enabling ciliary exit.

KEYWORDS:

BBSome; cilia; trafficking

PMID:
31303482
PMCID:
PMC6726506
[Available on 2020-09-03]
DOI:
10.1016/j.str.2019.06.006

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