Imperfect interface of Beclin1 coiled-coil domain regulates homodimer and heterodimer formation with Atg14L and UVRAG.
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.
Department of Applied Biology and Chemical Technology, State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China.
Xiaohua
X
Li
Liqiang
L
He
Ka Hing
KH
Che
Sarah F
SF
Funderburk
Lifeng
L
Pan
Nina
N
Pan
Mingjie
M
Zhang
Zhenyu
Z
Yue
Yanxiang
Y
Zhao
D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D058546:Class III Phosphatidylinositol 3-Kinases / Q000737:chemistry; D018360:Crystallography, X-Ray / Q000379:methods; D019281:Dimerization; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D013696:Temperature; D025521:Tumor Suppressor Proteins / Q000737:chemistry*
C539000:ATG14 protein, human; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; D000071183:Autophagy-Related Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; C408122:UVRAG protein, human; D058546:Class III Phosphatidylinositol 3-Kinases