Structure and Function of the gamma-Secretase Complex.

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Wolfe MS

Structure and Function of the gamma-Secretase Complex.

Biochemistry. 2019 Jul 9;58(27):2953-2966. doi: 10.1021/acs.biochem.9b00401. Epub 2019 Jun 25.

PubMed ID

31198028 [ View in PubMed

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Abstract

gamma-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 gamma-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 gamma-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 gamma-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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Nirogacestat	Presenilin-1	Protein	Humans	Yes	Inhibitor	Details