ArticleNature communications2014
Familial Alzheimer's mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site.
Article in Nature communications, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed.
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- Pathological calcium influx through amyloid beta pores disrupts synaptic function.Cell calcium · 2025Article
- Transient cholesterol interactions with the amyloid precursor protein involved in Alzheimer's disease pathogenesis.Biophysical reviews · 2025Review
- The interaction between neurotransmitter receptor activity and amyloid-β pathology in Alzheimer's disease.Journal of Alzheimer's disease : JAD · 2025Review
- Signs of Alzheimer's Disease: Tied to Aging.International journal of molecular sciences · 2025Review
- Helix-to-sheet transition of the Aβ42 peptide revealed using an enhanced sampling strategy and Markov state model.Computational and structural biotechnology journal · 2024Article
- Advances in the cell biology of the trafficking and processing of amyloid precursor protein: impact of familial Alzheimer's disease mutations.The Biochemical journal · 2024Review
- Low glucose induced Alzheimer's disease-like biochemical changes in human induced pluripotent stem cell-derived neurons is due to dysregulated O-GlcNAcylation.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2023Article
- Interaction of Substrates with γ-Secretase at the Level of Individual Transmembrane Helices-A Methodological Approach.International journal of molecular sciences · 2023Article
- Covalent fragment inhibits intramembrane proteolysis.Frontiers in molecular biosciences · 2022Article
- Effect of Cholesterol on C99 Dimerization: Revealed by Molecular Dynamics Simulations.Frontiers in molecular biosciences · 2022Article
- Structural Studies Providing Insights into Production and Conformational Behavior of Amyloid-β Peptide Associated with Alzheimer's Disease Development.Molecules (Basel, Switzerland) · 2021Review
- A trimeric hydrophobic zipper mediates the intramembrane assembly of SARS-CoV-2 spike.bioRxiv : the preprint server for biology · 2021Article
- Bicelles Rich in both Sphingolipids and Cholesterol and Their Use in Studies of Membrane Proteins.Journal of the American Chemical Society · 2020Article
- Substrate interaction inhibits γ-secretase production of amyloid-β peptides.Chemical communications (Cambridge, England) · 2020Article
- Targeting Amyloidogenic Processing of APP in Alzheimer's Disease.Frontiers in molecular neuroscience · 2020Review
- Substrate-Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype.Frontiers in molecular neuroscience · 2020Review
- Regulation of the alternative β-secretase meprin β by ADAM-mediated shedding.Cellular and molecular life sciences : CMLS · 2019Review
- Influence of the familial Alzheimer's disease-associated T43I mutation on the transmembrane structure and γ-secretase processing of the C99 peptide.The Journal of biological chemistry · 2019Article
- Processing of Mutant β-Amyloid Precursor Protein and the Clinicopathological Features of Familial Alzheimer's Disease.Aging and disease · 2019Review
Corrections and comments
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7 authors.
Funding
Abstract
The high Aβ42/Aβ40 production ratio is a hallmark of familial Alzheimer's disease, which can be caused by mutations in the amyloid precursor protein (APP). The C-terminus of Aβ is generated by γ-secretase cleavage within the transmembrane domain of APP (APPTM), a process that is primed by an initial ε-cleavage at either T48 or L49, resulting in subsequent production of Aβ42 or Aβ40, respectively. Here we solve the dimer structures of wild-type APPTM (AAPTM WT) and mutant APPTM (FAD mutants V44M) with solution NMR. The right-handed APPTM helical dimer is mediated by GXXXA motif. From the NMR structural and dynamic data, we show that the V44M and V44A mutations can selectively expose the T48 site by weakening helical hydrogen bonds and increasing hydrogen-deuterium exchange rate (kex). We propose a structural model in which FAD mutations (V44M and V44A) can open the T48 site γ-secretase for the initial ε-cleavage, and consequently shift cleavage preference towards Aβ42.
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