Crystal structure and biochemical analyses reveal Beclin 1 as a novel membrane binding protein.
The Beclin 1 gene is a haplo-insufficient tumor suppressor and plays an essential role in autophagy. However, the molecular mechanism by which Beclin 1 functions remains largely unknown. Here we report the crystal structure of the evolutionarily conserved domain (ECD) of Beclin 1 at 1.6 Å resolution. Beclin 1 ECD exhibits a previously unreported fold, with three structural repeats arranged symmetrically around a central axis. Beclin 1 ECD defines a novel class of membrane-binding domain, with a strong preference for lipid membrane enriched with cardiolipin. The tip of a surface loop in Beclin 1 ECD, comprising three aromatic amino acids, acts as a hydrophobic finger to associate with lipid membrane, consequently resulting in the deformation of membrane and liposomes. Mutation of these aromatic residues rendered Beclin 1 unable to stably associate with lipid membrane in vitro and unable to fully rescue autophagy in Beclin 1-knockdown cells in vivo. These observations form an important framework for deciphering the biological functions of Beclin 1.
Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China.
Weijiao
W
Huang
Wooyoung
W
Choi
Wanqiu
W
Hu
Na
N
Mi
Qiang
Q
Guo
Meisheng
M
Ma
Mei
M
Liu
Yuan
Y
Tian
Peilong
P
Lu
Feng-Liang
FL
Wang
Haiteng
H
Deng
Lei
L
Liu
Ning
N
Gao
Li
L
Yu
Yigong
Y
Shi
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000071186:Beclin-1; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins