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

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.

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Figure 1: TMP21 co-precipitates with other presenilin complex components.
Figure 2: Knockdown of TMP21 increases Aβ production.
Figure 3: Complementation of TMP21-deficient presenilin complexes (TMP21 siRNA) by exogenous immunopurified TMP21 (+ TMP21-Flag) reverts γ-secretase activity towards levels observed in wild-type control complexes (Control siRNA).
Figure 4: The ε-secretase cleavage site is not affected by knockdown of TMP21.

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Acknowledgements

We thank I. Schulz for the anti-TMP21 antibody, and F. T. Wieland for the anti-p24a antibody. This study was supported by grants from the Canadian Institutes of Health Research, the Howard Hughes Medical Institute, Canadian Institutes of Health Research–Japan Science and Technology Trust, the Alzheimer Society of Ontario, the Ontario Research and Development Challenge Fund and the Canada Foundation for Innovation. Author Contributions All authors contributed fully to the design, analysis and interpretation of the experiments described in this report.

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Correspondence to Peter St George-Hyslop.

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Chen, F., Hasegawa, H., Schmitt-Ulms, G. et al. TMP21 is a presenilin complex component that modulates γ-secretase but not ɛ-secretase activity. Nature 440, 1208–1212 (2006). https://doi.org/10.1038/nature04667

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