Imperfect interface of Beclin1 coiled-coil domainregulates homodimer and heterodimer formationwith Atg14L and UVRAG

摘要

Beclin 1 is a core component of the Class III Phosphatidylinositol 3-Kinase VPS34 complex.The coiled coil domain of Beclin 1 serves as an interaction platform for assembly of distinctAtg14L- and UVRAG-containing complexes to modulate VPS34 activity. Here we report thecrystal structure of the coiled coil domain that forms an antiparallel dimer and is renderedmetastable by a series of ‘ imperfect ’ a - d ’ pairings at its coiled coil interface. Atg14L and UVRAG promote the transition of metastable homodimeric Beclin 1 to heterodimeric Beclin1-Atg14L / UVRAG assembly. Beclin 1 mutants with their ‘ imperfect ’ a - d ’ pairings modified to enhanceself-interaction, show distinctively altered interactions with Atg14L or UVRAG. These resultssuggest that specific utilization of the dimer interface and modulation of the homodimer –heterodimer transition by Beclin 1-interacting partners may underlie the molecular mechanismthat controls the formation of various Beclin1 – VPS34 subcomplexes to exert their effect on anarray of VPS34-related activities, including autophagy.