期刊
CELL RESEARCH
卷 22, 期 3, 页码 473-489出版社
SPRINGERNATURE
DOI: 10.1038/cr.2012.24
关键词
Beclin 1; autophagy; crystal structure; membrane binding; membrane deformation; omegasome
类别
资金
- Ministry of Science and Technology [2009CB918801, 2010CB833704, 2011CB910100, 2010CB912402]
- National Natural Science Foundation of China [30888001, 30971484, 31030043]
- Tsinghua University [2010THZ0, 2009THZ03071]
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 angstrom 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.
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