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Substrate specificity of γ-secretase and other intramembrane proteases

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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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Correspondence to C. R. Sanders.

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Received 4 October 2007; received after revision 1 December 2007; accepted 7 December 2007

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Beel, A.J., Sanders, C.R. Substrate specificity of γ-secretase and other intramembrane proteases. Cell. Mol. Life Sci. 65, 1311–1334 (2008).

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