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Mol Cell. 2019 Jan 17;73(2):339-353.e6. doi: 10.1016/j.molcel.2018.10.035. Epub 2018 Dec 20.

Bidirectional Control of Autophagy by BECN1 BARA Domain Dynamics.

Author information

1
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA.
2
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
3
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, 60438 Frankfurt/M, Germany.
4
Department of Genetics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
5
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, 60438 Frankfurt/M, Germany; Institute of Biophysics, Goethe University, 60438 Frankfurt/M, Germany.
6
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: jimhurley@berkeley.edu.

Abstract

Membrane targeting of the BECN1-containing class III PI 3-kinase (PI3KC3) complexes is pivotal to the regulation of autophagy. The interaction of PI3KC3 complex II and its ubiquitously expressed inhibitor, Rubicon, was mapped to the first β sheet of the BECN1 BARA domain and the UVRAG BARA2 domain by hydrogen-deuterium exchange and cryo-EM. These data suggest that the BARA β sheet 1 unfolds to directly engage the membrane. This mechanism was confirmed using protein engineering, giant unilamellar vesicle assays, and molecular simulations. Using this mechanism, a BECN1 β sheet-1 derived peptide activates both PI3KC3 complexes I and II, while HIV-1 Nef inhibits complex II. These data reveal how BECN1 switches on and off PI3KC3 binding to membranes. The observations explain how PI3KC3 inhibition by Rubicon, activation by autophagy-inducing BECN1 peptides, and inhibition by HIV-1 Nef are mediated by the switchable ability of the BECN1 BARA domain to partially unfold and insert into membranes.

PMID:
30581147
PMCID:
PMC6450660
[Available on 2020-01-17]
DOI:
10.1016/j.molcel.2018.10.035
[Indexed for MEDLINE]

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