ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2019
Conformational Dynamics of Transmembrane Domain 3 of Presenilin 1 Is Associated with the Trimming Activity of γ-Secretase.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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Who cites it
6 citing papers in PubMed, 13 citations in OpenAlex.
- Article
- Different transmembrane domains determine the specificity and efficiency of the cleavage activity of the γ-secretase subunit presenilin.The Journal of biological chemistry · 2023Article
- Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene.International journal of molecular sciences · 2022Review
- Effects of the Notch Signaling Pathway on Secondary Brain Changes Caused by Spinal Cord Injury in Mice.Neurochemical research · 2022Article
- Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides.The Journal of biological chemistryArticle
- γ-secretase targeting in Alzheimer's disease.Journal of Alzheimer's disease reportsReview
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
γ-Secretase is an intramembrane-cleaving protease that generates the toxic species of the amyloid-β peptide (Aβ) that is responsible for the pathology of Alzheimer disease. The catalytic subunit of γ-secretase is presenilin 1 (PS1), which is a polytopic membrane protein with a hydrophilic catalytic pore. The length of the C terminus of Aβ is proteolytically determined by its processive trimming by γ-secretase, although the precise mechanism still remains largely unknown. Here, we identified that transmembrane domain (TMD) 3 of human PS1 is involved in the formation of the intramembranous hydrophilic pore. Notably, the water accessibility of TMD3 was greatly altered by point mutations and compounds, which modify γ-secretase activity. The changes in the water accessibility of TMD3 was also correlated with Aβ42 production. Moreover, crosslinking between TMD3 and TMD7 resulted in a loss of sensitivity to a γ-secretase modulator that reduces Aβ42 production. Therefore, our findings indicate that the conformational dynamics of TMD3 is a prerequisite for regulation of the Aβ trimming activity of γ-secretase.
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