Substrate specificity of γ-secretase and other intramembrane proteases

• Published in: Cellular and molecular life sciences : CMLS Vol. 65; no. 9; pp. 1311 - 1334
• Main Authors: Beel, A. J, Sanders, C. R
• Format: Journal Article
• Language: English
• Published: Basel Basel : SP Birkhäuser Verlag Basel 01.05.2008; SP Birkhäuser Verlag Basel
• Subjects: Alzheimer disease; Amino Acid Sequence; Amyloid beta-Protein Precursor - metabolism; amyloid precursor protein; Amyloid Precursor Protein Secretases - analysis; Amyloid Precursor Protein Secretases - chemistry; Amyloid Precursor Protein Secretases - metabolism; Animals; Aspartic Acid Endopeptidases - chemistry; Aspartic Acid Endopeptidases - metabolism; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Membrane - enzymology; I-CLiP; Intramembrane; Life Sciences; lipid raft; Membrane Microdomains - enzymology; Metalloproteases - chemistry; Metalloproteases - metabolism; Molecular Sequence Data; Peptide Hydrolases - metabolism; presenilin; protease; proteolysis; Review; rhomboid; S2P; secretase; Serine Endopeptidases - chemistry; Serine Endopeptidases - metabolism; substrate; Substrate Specificity; protease; S2P; lipid raft; Intramembrane; Alzheimer’s disease; amyloid precursor protein; presenilin; secretase; rhomboid; proteolysis; substrate; I-CLiP
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-008-7462-2

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.