Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 65, Issue 9, Pages 1311-1334Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-008-7462-2
Keywords
intramembrane; protease; proteolysis; secretase; rhomboid; substrate; S2P amyloid precursor protein; I-CLiP; Alzheimer's disease; lipid raft; presenilin
Categories
Funding
- NIA NIH HHS [R21 AG026581-02, R21 AG026581] Funding Source: Medline
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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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