TMP21 is a presenilin complex component that modulates γ-secretase but not ɛ-secretase activity

Fusheng Chen, Hiroshi Hasegawa, Gerold Schmitt-Ulms, Toshitaka Kawarai, Christopher Bohm, Taiichi Katayama, Yongjun Gu, Nobuo Sanjo, Michael Glista, Ekaterina Rogaeva, Yosuke Wakutani, Raphaëlle Pardossi-Piquard, Xueying Ruan, Anurag Tandon, Frédéric Checler, Philippe Marambaud, Kirk Hansen, David Westaway, Peter St George-Hyslop () and Paul Fraser
Additional contact information
Fusheng Chen: University of Toronto
Hiroshi Hasegawa: University of Toronto
Gerold Schmitt-Ulms: University of Toronto
Toshitaka Kawarai: University of Toronto
Christopher Bohm: University of Toronto
Taiichi Katayama: University of Toronto
Yongjun Gu: University of Toronto
Nobuo Sanjo: University of Toronto
Michael Glista: University of Toronto
Ekaterina Rogaeva: University of Toronto
Yosuke Wakutani: University of Toronto
Raphaëlle Pardossi-Piquard: University of Toronto
Xueying Ruan: University of Toronto
Anurag Tandon: University of Toronto
Frédéric Checler: UMR6097CNRS/UNSA, Equipe labellisée FRM
Philippe Marambaud: Albert Einstein College of Medicine
Kirk Hansen: University of California
David Westaway: University of Toronto
Peter St George-Hyslop: University of Toronto
Paul Fraser: University of Toronto

Nature, 2006, vol. 440, issue 7088, 1208-1212

Abstract: Abstract The presenilin proteins (PS1 and PS2)1,2 and their interacting partners nicastrin3, aph-1 (refs 4, 5) and pen-2 (ref. 5) form a series of high-molecular-mass, membrane-bound protein complexes6,7,8 that are necessary for γ-secretase and ɛ-secretase cleavage of selected type 1 transmembrane proteins, including the amyloid precursor protein9, Notch10 and cadherins11. Modest cleavage activity can be generated by reconstituting these four proteins in yeast and Spodoptera frugiperda (sf9) cells12,13,14. However, a critical but unanswered question about the biology of the presenilin complexes is how their activity is modulated in terms of substrate specificity and/or relative activities at the γ and ɛ sites. A corollary to this question is whether additional proteins in the presenilin complexes might subsume these putative regulatory functions. The hypothesis that additional proteins might exist in the presenilin complexes is supported by the fact that enzymatically active complexes have a mass that is much greater than predicted for a 1:1:1:1 stoichiometric complex (at least 650 kDa observed, compared with about 220 kDa predicted)6,7,8. To address these questions we undertook a search for presenilin-interacting proteins that differentially affected γ- and ɛ-site cleavage events. Here we report that TMP21, a member of the p24 cargo protein family, is a component of presenilin complexes and differentially regulates γ-secretase cleavage without affecting ɛ-secretase activity.

Date: 2006
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DOI: 10.1038/nature04667

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