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Title: Presenilin modulates Pen-2 levels posttranslationally by protecting it from proteasomal degradation
Authors: Crystal, AS
Morais, Vanessa
Fortna, RR
Carlin, D
Pierson, TC
Wilson, CA
Lee, VMY
Doms, RW # ×
Issue Date: Mar-2004
Publisher: American Chemical Society
Series Title: Biochemistry vol:43 issue:12 pages:3555-3563
Abstract: The gamma-secretase complex functions to cleave several type I transmembrane proteins within their transmembrane domains. These include the amyloid precursor protein, which is central to Alzheimer's disease pathogenesis, as well as N-cadherin and Notch, which regulate transcription. This complex is composed of four requisite integral membrane proteins: presenilin 1 (PSI) or presenilin 2 (PS2), nicastrin, Pen-2, and Aph-1. How these proteins coordinately regulate one another and assemble to form a functional complex is not well understood. In this report we demonstrate that PS1 selectively enhances the stability of Pen-2 protein but not that of nicastrin or Aph-1. In the absence of PS 1, Pen-2 was rapidly degraded by the proteasome. As PS1 levels increased, so too did the half-life of Pen-2 and therefore its steady-state levels. In addition, Pen-2 protein levels correlated with PS1 levels not only in cell culture but in transgenic mouse models as well. The genetic absence of PS1 and PS2, and therefore of gamma-secretase-dependent mediation of transcriptional activity, did not affect Pen-2 mRNA levels. Rather, presenilin (PS) regulates Pen-2 levels posttranslationally by preventing its degradation by the proteasome. Thus, the amount of Pen-2 protein is effectively titrated by its PS binding partner, and the rapidity with which Pen-2 is degraded in the absence of PS interactions could provide a mechanism to tightly regulate gamma-secretase complex assembly.
ISSN: 0006-2960
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for the Research of Neurodegenerative Diseases
× corresponding author
# (joint) last author

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