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| Title | Bidirectional Control of Autophagy by BECN1 BARA Domain Dynamics. |
|---|---|
| Journal, issue, pages | Mol Cell, Vol. 73, Issue 2, Page 339-353.e6, Year 2019 |
| Publish date | Jan 17, 2019 |
 Authors | Chunmei 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 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 ...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 links | Mol Cell / PubMed:30581147 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 6.8 Å |
| Structure data |  EMDB-8993: |
| Source |
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Homo sapiens (human)
