Substrate specificity of gamma-secretase and other intramembrane proteases.
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.
Beel
A J
AJ
Department of Biochemistry and Center for Structural Biology, Vanderbilt University School of Medicine, Rm. 5142 MRBIII, 21st Ave. S., Nashville, Tennessee 37232-8725, USA.
Sanders
C R
CR
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology*; D021962:Membrane Microdomains / Q000201:enzymology; D045726:Metalloproteases / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D045726:Metalloproteases; D010447:Peptide Hydrolases; D012697:Serine Endopeptidases; D016282:Aspartic Acid Endopeptidases