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Recognition of the Amyloid Precursor Protein by Human γ-secretase

Recognition of the Amyloid Precursor Protein by Human γ-secretase

Rui Zhou, Guanghui Yang, Xuefei Guo, Qiang Zhou, Jianlin Lei, Yigong Shi

Science. 2019 Feb 15;363(6428):eaaw0930.

PMID: 30630874

Abstract:

Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase is linked to Alzheimer's disease (AD). We report an atomic structure of human γ-secretase in complex with a transmembrane (TM) APP fragment at 2.6-angstrom resolution. The TM helix of APP closely interacts with five surrounding TMs of PS1 (the catalytic subunit of γ-secretase). A hybrid β sheet, which is formed by a β strand from APP and two β strands from PS1, guides γ-secretase to the scissile peptide bond of APP between its TM and β strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from AD patients. This structure, together with that of γ-secretase bound to Notch, reveal contrasting features of substrate binding, which may be applied toward the design of substrate-specific inhibitors.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248115	β-Secretase human			Price

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