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

@article{Chen2006TMP21IA,
  title={TMP21 is a presenilin complex component that modulates $\gamma$-secretase but not ɛ-secretase activity},
  author={Fusheng Chen and Hiroshi Hasegawa and Gerold Schmitt-Ulms and Toshitaka Kawarai and Christopher Bohm and Taiichi Katayama and Yongjun Gu and Nobuo Sanjo and Michael J. Glista and Ekaterina Rogaeva and Yosuke Wakutani and Rapha{\"e}lle Pardossi-Piquard and Xueying Ruan and Anurag Tandon and Fr{\'e}d{\'e}ric Checler and Philippe Marambaud and Kirk C. Hansen and David Westaway and Peter St. George-Hyslop and Paul E. Fraser},
  journal={Nature},
  year={2006},
  volume={440},
  pages={1208-1212}
}
The presenilin proteins (PS1 and PS2) and their interacting partners nicastrin, aph-1 (refs 4, 5) and pen-2 (ref. 5) form a series of high-molecular-mass, membrane-bound protein complexes that are necessary for γ-secretase and ɛ-secretase cleavage of selected type 1 transmembrane proteins, including the amyloid precursor protein, Notch and cadherins. Modest cleavage activity can be generated by reconstituting these four proteins in yeast and Spodoptera frugiperda (sf9) cells. However, a… 

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TLDR
The results suggest that the conserved transmembrane histidine residues contribute to APH1 function and can affect presenilin catalytic activity.
Substrate recruitment by γ-secretase.
Structural and Chemical Biology of Presenilin Complexes.
TLDR
Taken together, these studies suggest that the presenilin complex exists in several conformations, and subtle long-range (allosteric) shifts in the conformation of the complex underpin substrate access to the catalytic site and the mechanism of action for allosteric inhibitors and modulators.
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TLDR
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