The catalytic core of gamma-secretase: presenilin revisited.
Mutations in the presenilin 1 (PS1) gene are the major cause of familial Alzheimer s disease (AD). They effect an increased production of the highly neurotoxic 42 amino acid variant of the amyloid-beta peptide (Abeta), which is believed to initiate the disease. Abeta is the product of two consecutive cleavages of the beta-amyloid precursor protein (APP) by two proteases, beta-secretase and gamma-secretase. The latter enzyme has been identified as an intramembrane-cleaving multiprotein complex that apart from APP cleaves a large number of other type I transmembrane proteins. PS1 and its homologue PS2 are essential for gamma-secretase cleavage and more than a decade after their discovery it is now firmly established that they function as catalytic subunits of gamma-secretase. This review recapitulates the findings that led to this conclusion as well as the further progress made on the function of PS as gamma-secretase since then.
Steiner
Harald
H
Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Schil-lerstr. 44, Ludwig-Maximilians-University, 80336 Munich, Germany. harald.steiner@med.uni-muenchen.de
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D006801:Humans; D008969:Molecular Sequence Data; D053763:Presenilins / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D013379:Substrate Specificity
D016564:Amyloid beta-Protein Precursor; D053763:Presenilins; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases