ArticleProceedings of the National Academy of Sciences of the United States of America2015
Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 47 citations in OpenAlex.
- Precision Medicine in Neurodegenerative Diseases: Genomic Approaches to Target Amyloid-β, Tau, and Alpha-Synuclein Pathways.Current genomics · 2025Review
- Altered copper transport in oxidative stress-dependent brain endothelial barrier dysfunction associated with Alzheimer's disease.Vascular pharmacology · 2024Article
- The generation of detergent-insoluble clipped fragments from an ERAD substrate in mammalian cells.Scientific reports · 2023Article
- Probing the Mechanisms of Inhibitors Binding to Presenilin Homologue Using Molecular Dynamics Simulations.Molecules (Basel, Switzerland) · 2023Article
- Article
- The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases.International journal of molecular sciences · 2022Review
- Covalent fragment inhibits intramembrane proteolysis.Frontiers in molecular biosciences · 2022Article
- Preparation of a Deuterated Membrane Protein for Small-Angle Neutron Scattering.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Substrate interaction inhibits γ-secretase production of amyloid-β peptides.Chemical communications (Cambridge, England) · 2020Article
- A Mass-Spectrometry-Based Approach to Distinguish Annular and Specific Lipid Binding to Membrane Proteins.Angewandte Chemie (International ed. in English) · 2020Article
- Targeting Amyloidogenic Processing of APP in Alzheimer's Disease.Frontiers in molecular neuroscience · 2020Review
- Bax inhibitor 1 is a γ-secretase-independent presenilin-binding protein.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Proteolytic systems of archaea: slicing, dicing, and mincing in the extreme.Emerging topics in life sciences · 2018Article
- Coupled Transmembrane Substrate Docking and Helical Unwinding in Intramembrane Proteolysis of Amyloid Precursor Protein.Scientific reports · 2018Article
- Unwinding of the Substrate Transmembrane Helix in Intramembrane Proteolysis.Biophysical journal · 2018Article
- Both positional and chemical variables controlThe Journal of biological chemistry · 2018Article
- Solution Structure of an Intramembrane Aspartyl Protease via Small Angle Neutron Scattering.Biophysical journal · 2018Article
- Characterizing the structural ensemble of γ-secretase using a multiscale molecular dynamics approach.Chemical science · 2017Article
- Identification of inhibitors of the transmembrane protease FlaK of Methanococcus maripaludis.MicrobiologyOpen · 2016Article
- Nicastrin guards Alzheimer's gate.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.