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Recognition of the Amyloid Precursor Protein by Human gamma-secretase
Structural highlights
DiseaseNICA_HUMAN Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. FunctionNICA_HUMAN Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor required for the assembly of the gamma-secretase complex. Publication Abstract from PubMedCleavage of amyloid precursor protein (APP) by the intramembrane protease gamma-secretase is linked to Alzheimer's disease (AD). We report an atomic structure of human gamma-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 gamma-secretase). A hybrid beta sheet, which is formed by a beta strand from APP and two beta strands from PS1, guides gamma-secretase to the scissile peptide bond of APP between its TM and beta strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from AD patients. This structure, together with that of gamma-secretase bound to Notch, reveal contrasting features of substrate binding, which may be applied toward the design of substrate-specific inhibitors. Recognition of the amyloid precursor protein by human gamma-secretase.,Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y Science. 2019 Feb 15;363(6428). pii: science.aaw0930. doi:, 10.1126/science.aaw0930. Epub 2019 Jan 10. PMID:30630874[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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