Architecture and Dynamics of the Autophagic Phosphatidylinositol 3-Kinase Complex

作者：Baskaran, Sulochanadevi; Carlson, Lars-Anders; Stjepanovic, Goran; Young, Lindsey N.; Kim, Do Jin; Grob, Patricia; Stanley, Robin E.; Nogales, Eva^*; Hurley, James H.

来源：eLife, 2014, 3: e05115.

DOI：10.7554/eLife.05115

• CRYSTAL-STRUCTURE
• BECLIN 1
• ELECTRON-MICROSCOPY
• PROTEINS
• DOMAIN
• VISUALIZATION
• BIOGENESIS
• SUBUNIT
• NETWORK
• RUBICON

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 that regulate PI3KC3 activity, resides near the pivot point. These observations provide a framework for understanding the allosteric regulation of lipid kinase activity.

• 出版日期2014-12-9
• 单位NIH