Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex

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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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Sulochanadevi Baskaran

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

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The authors declare that no competing interests exist.
Lars-Anders Carlson

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

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The authors declare that no competing interests exist.
Goran Stjepanovic

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

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The authors declare that no competing interests exist.
Lindsey N Young

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

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The authors declare that no competing interests exist.
Do Jin Kim

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

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Patricia Grob

Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States

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Robin E Stanley

National Institutes of Health, Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States

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Eva Nogales

Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States

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James H Hurley

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

For correspondence
jimhurley@berkeley.edu

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The authors declare that no competing interests exist.

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This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.