Bidirectional Control of Autophagy by BECN1 BARA Domain Dynamics
- PMID: 30581147
- PMCID: PMC6450660
- DOI: 10.1016/j.molcel.2018.10.035
Bidirectional Control of Autophagy by BECN1 BARA Domain Dynamics
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.
Copyright © 2018 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of Interests
C.C., L.Y.N., J.H.H., and UC Berkeley have applied for patents for protein constructs and assays related to this work. J.H.H. is a founder of Casma Therapeutics.
Figures
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Comment in
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The BARA necessities of PtdIns 3-kinase activation in autophagy.Autophagy. 2019 Jun;15(6):1122-1123. doi: 10.1080/15548627.2019.1596501. Epub 2019 Mar 30. Autophagy. 2019. PMID: 30894086 Free PMC article.
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