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Cell Mol Life Sci. 2008 May;65(9):1311-34. doi: 10.1007/s00018-008-7462-2.

Substrate specificity of gamma-secretase and other intramembrane proteases.

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Department of Biochemistry and Center for Structural Biology, Vanderbilt University School of Medicine, Rm. 5142 MRBIII, 21st Ave. S., Nashville, Tennessee 37232-8725, USA.


Gamma-Secretase is a promiscuous protease that cleaves bitopic membrane proteins within the lipid bilayer. Elucidating both the mechanistic basis of gamma-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 gamma-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 gamma-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 gamma-secretase and its substrates, we also survey the voluminous body of literature concerning the traffic of gamma-secretase and its most prominent substrate, the amyloid precursor protein.

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