ArticleThe Journal of biological chemistry2014
Perturbations of the straight transmembrane α-helical structure of the amyloid precursor protein affect its processing by γ-secretase.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 42 citations in OpenAlex.
- Alzheimer's Disease Etiology Hypotheses and Therapeutic Strategies: A Perspective.International journal of molecular sciences · 2025Review
- Article
- Bicelles Rich in both Sphingolipids and Cholesterol and Their Use in Studies of Membrane Proteins.Journal of the American Chemical Society · 2020Article
- Modulating Hinge Flexibility in the APP Transmembrane Domain Alters γ-Secretase Cleavage.Biophysical journal · 2019Article
- Self-Assembly of Polymer-Encased Lipid Nanodiscs and Membrane Protein Reconstitution.The journal of physical chemistry. B · 2019Article
- Emerging Diversity in Lipid-Protein Interactions.Chemical reviews · 2019Review
- Dissecting conformational changes in APP's transmembrane domain linked to ε-efficiency in familial Alzheimer's disease.PloS one · 2018Article
- Backbone Hydrogen Bond Strengths Can Vary Widely in Transmembrane Helices.Journal of the American Chemical Society · 2017Article
- Structural and biochemical differences between the Notch and the amyloid precursor protein transmembrane domains.Science advances · 2017Article
- Impact of membrane lipid composition on the structure and stability of the transmembrane domain of amyloid precursor protein.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Rotameric preferences of a protein spin label at edge-strand β-sheet sites.Protein science : a publication of the Protein Society · 2016Article
- Lost region in amyloid precursor protein (APP) through TALEN-mediated genome editing alters mitochondrial morphology.Scientific reports · 2016Article
- Impact of bilayer lipid composition on the structure and topology of the transmembrane amyloid precursor C99 protein.Journal of the American Chemical Society · 2014Article
- Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase.Frontiers in physiology · 2014Review
- Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations.PloS one · 2014Article
- The C99 domain of the amyloid precursor protein resides in the disordered membrane phase.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The amyloid precursor protein (APP) is a widely expressed type I transmembrane (TM) glycoprotein present at the neuronal synapse. The proteolytic cleavage by γ-secretase of its C-terminal fragment produces amyloid-β (Aβ) peptides of different lengths, the deposition of which is an early indicator of Alzheimer disease. At present, there is no consensus on the conformation of the APP-TM domain at the biological membrane. Although structures have been determined by NMR in detergent micelles, their conformation is markedly different. Here we show by using molecular simulations that the APP-TM region systematically prefers a straight α-helical conformation once embedded in a membrane bilayer. However, APP-TM is highly flexible, and its secondary structure is strongly influenced by the surrounding lipid environment, as when enclosed in detergent micelles. This behavior is confirmed when analyzing in silico the atomistic APP-TM population observed by residual dipolar couplings and double electron-electron resonance spectroscopy. These structural and dynamic features are critical in the proteolytic processing of APP by the γ-secretase enzyme, as suggested by a series of Gly(700) mutants. Affecting the hydration and flexibility of APP-TM, these mutants invariantly show an increase in the production of Aβ38 compared with Aβ40 peptides, which is reminiscent of the effect of γ-secretase modulators inhibitors.
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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.