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Journal Article

Bidirectional Control of Autophagy by BECN1 BARA Domain Dynamics

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Bülow,  Sören von       
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;

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Hummer,  Gerhard       
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;
Institute of Biophysics, Goethe University, Frankfurt, Germany;

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Citation

Chang, C., Young, L. N., Morris, K. L., Bülow, S. v., Schöneberg, J., Yamamoto-Imoto, H., et al. (2019). Bidirectional Control of Autophagy by BECN1 BARA Domain Dynamics. Molecular Cell, 73(2), 339-353. doi:10.1016/j.molcel.2018.10.035.


Cite as: https://hdl.handle.net/21.11116/0000-0002-E3EE-2
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.