Imperfect interface of Beclin1 coiled-coil domain regulates homodimer and heterodimer formation with Atg14L and UVRAG

Xiaohua Li, Liqiang He, Ka Hing Che, Sarah F. Funderburk, Lifeng Pan, Nina Pan, Mingjie Zhang, Zhenyu Yue () and Yanxiang Zhao ()
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Xiaohua Li: State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China.
Liqiang He: Mount Sinai School of Medicine, Friedman Brain Institute
Ka Hing Che: State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China.
Sarah F. Funderburk: Mount Sinai School of Medicine, Friedman Brain Institute
Lifeng Pan: State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, PR China.
Nina Pan: Mount Sinai School of Medicine, Friedman Brain Institute
Mingjie Zhang: State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, PR China.
Zhenyu Yue: Mount Sinai School of Medicine, Friedman Brain Institute
Yanxiang Zhao: State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China.

Nature Communications, 2012, vol. 3, issue 1, 1-11

Abstract: Abstract 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 distinct Atg14L- and UVRAG-containing complexes to modulate VPS34 activity. Here we report the crystal structure of the coiled coil domain that forms an antiparallel dimer and is rendered metastable 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 enhance self-interaction, show distinctively altered interactions with Atg14L or UVRAG. These results suggest that specific utilization of the dimer interface and modulation of the homodimer–heterodimer transition by Beclin 1-interacting partners may underlie the molecular mechanism that controls the formation of various Beclin1–VPS34 subcomplexes to exert their effect on an array of VPS34-related activities, including autophagy.

Date: 2012
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DOI: 10.1038/ncomms1648

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