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PMID: 18239854 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Substrate specificity of gamma-secretase and other intramembrane proteases.

Cellular and molecular life sciences : CMLS ·Vol. 65 ·No. 9 ·2008-05-00 ·Pages 1311-34

Beel AJ, Sanders CR

Abstract

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.

MeSH Terms
Amino Acid Sequence Amyloid Precursor Protein Secretases/analysis,chemistry,metabolism Amyloid beta-Protein Precursor/metabolism Animals Aspartic Acid Endopeptidases/chemistry,metabolism Cell Membrane/enzymology Membrane Microdomains/enzymology Metalloproteases/chemistry,metabolism Molecular Sequence Data Peptide Hydrolases/metabolism Serine Endopeptidases/chemistry,metabolism Substrate Specificity
Chemicals
Amyloid beta-Protein Precursor Amyloid Precursor Protein Secretases Metalloproteases Peptide Hydrolases Serine Endopeptidases Aspartic Acid Endopeptidases
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Beel A J
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
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Article Info
Journal
Cellular and molecular life sciences : CMLS
Abbr.
Cell Mol Life Sci
ISSN
1420-682X
DOI
10.1007/s00018-008-7462-2
Published
2008-05-00
Pages
1311-34
Language
English
Region
Switzerland
NLM ID
9705402
PMCID
PMC2569971
Subset
IM
Grants
NIA NIH HHS · R21 AG026581 · United States
NIA NIH HHS · R21 AG026581-02 · United States
External Links
PubMed source DOI: 10.1007/s00018-008-7462-2 PMC Full Text View journal details
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