早老素
跨膜蛋白
蛋白酶
跨膜结构域
淀粉样前体蛋白分泌酶
脂质双层
生物化学
化学
突变
结构生物学
细胞生物学
劈开
淀粉样前体蛋白
酶
生物
生物物理学
膜
突变
阿尔茨海默病
疾病
医学
受体
病理
基因
出处
期刊:Biochemistry
[American Chemical Society]
日期:2019-06-14
卷期号:58 (27): 2953-2966
被引量:77
标识
DOI:10.1021/acs.biochem.9b00401
摘要
γ-Secretase is a membrane-embedded protease complex, with presenilin as the catalytic component containing two transmembrane aspartates in the active site. With more than 90 known substrates, the γ-secretase complex is considered "the proteasome of the membrane", with central roles in biology and medicine. The protease carries out hydrolysis within the lipid bilayer to cleave the transmembrane domain of the substrate multiple times before releasing secreted products. For many years, elucidation of γ-secretase structure and function largely relied on small-molecule probes and mutagenesis. Recently, however, advances in cryo-electron microscopy have led to the first detailed structures of the protease complex. Two new reports of structures of γ-secretase bound to membrane protein substrates provide great insight into the nature of substrate recognition and how Alzheimer's disease-causing mutations in presenilin might alter substrate binding and processing. These new structures offer a powerful platform for elucidating enzyme mechanisms, deciphering effects of disease-causing mutations, and advancing Alzheimer's disease drug discovery.
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