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Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex.

  • Author(s): Baskaran, Sulochanadevi
  • Carlson, Lars-Anders
  • Stjepanovic, Goran
  • Young, Lindsey N
  • Kim, Do Jin
  • Grob, Patricia
  • Stanley, Robin E
  • Nogales, Eva
  • Hurley, James H
  • et al.

Published Web Location

http://elifesciences.org/content/early/2014/12/09/eLife.05115
No data is associated with this publication.
Abstract

The class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1) that functions in early autophagy consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14. The structure of the ATG14-containing PI3KC3-C1 was determined by single-particle EM, revealing a V-shaped architecture. All of the ordered domains of VPS34, VPS15, and BECN1 were mapped by MBP tagging. The dynamics of the complex were defined using hydrogen-deuterium exchange, revealing a novel 20-residue ordered region C-terminal to the VPS34 C2 domain. VPS15 organizes the complex and serves as a bridge between VPS34 and the ATG14:BECN1 subcomplex. Dynamic transitions occur in which the lipid kinase domain is ejected from the complex and VPS15 pivots at the base of the V. The N-terminus of BECN1, the target for signaling inputs, resides near the pivot point. These observations provide a framework for understanding the allosteric regulation of lipid kinase activity.

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