Mutation of conserved aspartates affect maturation of presenilin 1 and presenilin 2 complexes

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Abstract:

Presenilin (PS1 and PS2) holoproteins are transiently incorporated into low molecular weight (MW) complexes. During subsequent incorporation into a higher MW complex, they undergo endoproteolysis to generate stable N- and C-terminal fragments (NTF/CTF). Mutation of either of two conserved aspartate residues in transmembrane domains inhibits both presenilin-endoproteolysis and the proteolytic processing of APP and Notch. We show that aspartate-mutant holoprotein presenilins are not incorporated into the high molecular weight, NTF/CTF-containing complexes. Aspartate-mutant presenilin holoproteins also preclude entry of endogenous wild-type PS1/PS2 into the high molecular weight complexes, but do not affect the incorporation of wild-type holoproteins into lower molecular weight holoprotein complexes. These data suggest that the loss-of-function aspartate-mutants cause altered PS complex maturation, and argue that the functional presenilin moieties are contained in the high molecular weight presenilin NTF/CTF-containing complexes.

Keywords: -secretase; Alzheimer Disease; amyloid -peptide; presenilin complexes

Document Type: Original Article

Affiliations: 1: Centre for Research in Neurodegenerative Diseases, Departments of Medical, Biophysics and Medicine, University of Toronto, and Department of Medicine, (Neurology), The University Health Network (Toronto Western Hospital), Toronto, Ontario, Canada, M5S 3H2, 2: Adolf-Butenandt Institut, Dept. of Biochemistry, Ludwig-Maximilians, University, Schillerstrasse 44, D-80336, Muenchen, Germany.

Publication date: December 1, 2000

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