Requirement for small side chain residues within the GxGD-motif of presenilin for γ-secretase substrate cleavage
Article first published online: 15 DEC 2009
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 112, Issue 4, pages 940–950, February 2010
How to Cite
Pérez-Revuelta, B. I., Fukumori, A., Lammich, S., Yamasaki, A., Haass, C. and Steiner, H. (2010), Requirement for small side chain residues within the GxGD-motif of presenilin for γ-secretase substrate cleavage. Journal of Neurochemistry, 112: 940–950. doi: 10.1111/j.1471-4159.2009.06510.x
- Issue published online: 20 JAN 2010
- Article first published online: 15 DEC 2009
- Received July 28, 2009; revised manuscript received November 5, 2009; accepted November 18, 2009.
- Alzheimer’s disease;
- GxGD-type protease;
- intramembrane proteolysis;
J. Neurochem. (2009) 112, 940–950.
γ-Secretase is a pivotal intramembrane-cleaving protease complex and important drug target for Alzheimer’s disease. The protease not only releases small peptides, such as the amyloid-β peptide, which drives Alzheimer’s disease pathogenesis, but also intracellular domains, which can have critical functions in nuclear signaling. Unlike typical aspartyl proteases, γ-secretase contains a non-classical GxGD active site motif in its catalytic subunit presenilin (PS) 1 or PS2. It is not known whether both glycines are of similar functional relevance and why the glycine residues are invariant elements of the motif. Here we identify the N-terminal glycine of the GxGD motif in PS1, G382, as a critical residue of the active site domain of γ-secretase. Substitution of G382 by a number of different amino acids abrogated γ-secretase activity. Only the smallest possible G382A substitution allowed substantial γ-secretase activity. Depending on the substrate, however, the presence of G382 could become even an absolute functional requirement of γ-secretase. Very similar results were obtained for the C-terminal glycine residue (G384) of the GxGD motif. Our data thus identify a requirement for small side chain residues in the active site domain of γ-secretase and suggest that the glycines of the GxGD motif could be evolutionary conserved to allow cleavage of all possible γ-secretase substrates, including those, which are highly sensitive to minimal alteration of the PS active site domain. These findings broaden our understanding of γ-secretase substrate recognition and cleavage, which may prove crucial for therapeutic targeting of the enzyme.