Vps34 Kinase Domain Dynamics Regulate the Autophagic PI 3-Kinase Complex

5 years ago

Vps34 Kinase Domain Dynamics Regulate the Autophagic PI 3-Kinase Complex

The class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1) is required for the initiation of essentially all macroautophagic processes. PI3KC3-C1 consists of the lipid kinase catalytic subunit VPS34, the VPS15 scaffold, and the regulatory BECN1 and ATG14 subunits. The VPS34 catalytic domain and BECN1:ATG14 subcomplex do not touch, and it is unclear how allosteric signals are transmitted to VPS34. We used EM and crosslinking mass spectrometry to dissect five conformational substates of the complex, including one in which the VPS34 catalytic domain is dislodged from the complex but remains tethered by an intrinsically disordered linker. A “leashed” construct prevented dislodging without interfering with the other conformations, blocked enzyme activity in vitro, and blocked autophagy induction in yeast cells. This pinpoints the dislodging and tethering of the VPS34 catalytic domain, and its regulation by VPS15, as a master allosteric switch in autophagy induction.

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Teaser

Stjepanovic et al. report how the class III phosphatidylinositol 3-kinase complex I of autophagy undergoes a series of conformational changes in which the VPS34 lipid kinase domain is first recruited via VPS15 scaffold protein, and then partially dissociates from the complex in order to access its lipid substrate. In this way, VPS15 acts as a master allosteric switch in autophagy induction.

Publisher URL: www.sciencedirect.com/science

DOI: S1097276517304975