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TitleBidirectional Control of Autophagy by BECN1 BARA Domain Dynamics.
Journal, issue, pagesMol Cell, Vol. 73, Issue 2, Page 339-353.e6, Year 2019
Publish dateJan 17, 2019
AuthorsChunmei Chang / Lindsey N Young / Kyle L Morris / Sören von Bülow / Johannes Schöneberg / Hitomi Yamamoto-Imoto / Yukako Oe / Kentaro Yamamoto / Shuhei Nakamura / Goran Stjepanovic / Gerhard Hummer / Tamotsu Yoshimori / James H Hurley /
PubMed AbstractMembrane 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 ...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.
External linksMol Cell / PubMed:30581147 / PubMed Central
MethodsEM (single particle)
Resolution6.8 Å
Structure data

EMDB-8993:
Class III PI3K Complex 2 with inhibitor Rubicon
Method: EM (single particle) / Resolution: 6.8 Å

Source
  • Homo sapiens (human)

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