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The substrate repertoire of γ-secretase/presenilin.

Semin Cell Dev Biol. 2020;S1084-9521(20)30003-3. doi:10.1016/j.semcdb.2020.05.019 [published online ahead of print, 2020 Jun 29]

Authors/Editors: Güner G, Lichtenthaler SF.
Publication Date: 2020

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Abstract

γ-Secretase is a promiscuous protease that cleaves bitopic membrane proteins within the lipid bilayer. Elucidating both the mechanistic basis of γ-secretase proteolysis and the precise factors regulating substrate identification is important because modulation of this biochemical degradative process can have important consequences in a physiological and pathophysiological context. Here, we briefly review such information for all major classes of intramembranously cleaving proteases (I-CLiPs), with an emphasis on γ-secretase, an I-CLiP closely linked to the etiology of Alzheimer’s disease. A large body of emerging data allows us to survey the substrates of γ-secretase to ascertain the conformational features that predispose a peptide to cleavage by this enigmatic protease. Because substrate specificity in vivo is closely linked to the relative subcellular compartmentalization of γ-secretase and its substrates, we also survey the voluminous body of literature concerning the traffic of γ-secretase and its most prominent substrate, the amyloid precursor protein.

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