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Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH
- Source :
- Proceedings of the National Academy of Sciences of the United States of America. 112(11)
- Publication Year :
- 2015
-
Abstract
- Aberrant cleavage of amyloid precursor protein (APP) by γ-secretase contributes to the development of Alzheimer’s disease. More than 200 disease-derived mutations have been identified in presenilin (the catalytic subunit of γ-secretase), making modulation of γ-secretase activity a potentially attractive therapeutic opportunity. Unfortunately, the technical challenges in dealing with intact γ-secretase have hindered discovery of modulators and demand a convenient substitute approach. Here we report that, similar to γ-secretase, the archaeal presenilin homolog PSH faithfully processes the substrate APP C99 into Aβ42, Aβ40, and Aβ38. The molar ratio of the cleavage products Aβ42 over Aβ40 by PSH is nearly identical to that by γ-secretase. The proteolytic activity of PSH is specifically suppressed by presenilin-specific inhibitors. Known modulators of γ-secretase also modulate PSH similarly in terms of the Aβ42/Aβ40 ratio. Structural analysis reveals association of a known γ-secretase inhibitor with PSH between its two catalytic aspartate residues. These findings identify PSH as a surrogate protease for the screening of agents that may regulate the protease activity and the cleavage preference of γ-secretase.
- Subjects :
- Multidisciplinary
Protease
biology
Sequence Homology, Amino Acid
Intramembrane protease
Protein subunit
medicine.medical_treatment
Molecular Sequence Data
Presenilins
Biological Sciences
Cleavage (embryo)
Archaea
Presenilin
Substrate Specificity
Amyloid beta-Protein Precursor
Biochemistry
Mutation
Amyloid precursor protein
biology.protein
medicine
Humans
Amino Acid Sequence
Amyloid Precursor Protein Secretases
Amyloid precursor protein secretase
Gamma secretase
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 112
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....2224951754875423145cd28b662d3525