ArticleProceedings of the National Academy of Sciences of the United States of America2016
Impact of membrane lipid composition on the structure and stability of the transmembrane domain of amyloid precursor protein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 94 citations in OpenAlex.
- Uncovering the biological mechanisms of TREM2 with molecular simulations: A comprehensive review and perspective.Progress in biophysics and molecular biology · 2026Review
- Accurate determination of the preferred aggregation number of a micelle-encapsulated membrane protein dimer.Biophysical journal · 2026Article
- Differential effects of lipid composition on the thermal and functional properties of membrane associated CYP2J2.Protein science : a publication of the Protein Society · 2026Article
- From mechanistic modeling to AI-driven design: computational strategies for targeting the γ-secretase complex.Briefings in bioinformatics · 2026Review
- Metagenomics reveals diverse community of putative mercury methylators across different biogeochemical niches in Sansha Yongle blue hole.Marine life science & technology · 2026Article
- Accurate determination of the preferred aggregation number of a micelle-encapsulated membrane protein dimer.bioRxiv : the preprint server for biology · 2025Article
- Transient cholesterol interactions with the amyloid precursor protein involved in Alzheimer's disease pathogenesis.Biophysical reviews · 2025Review
- Detergent-free isolation and characterization of amyloid precursor protein C99 in E. coli native lipid-nanodiscs using non-ionic polymer.Protein science : a publication of the Protein Society · 2025Article
- Diverse Interactions of Sterols with Amyloid Precursor Protein Transmembrane Domain Can Shift Distribution Between Alternative Amyloid-β Production Cascades in Manner Dependent on Local Lipid Environment.International journal of molecular sciences · 2025Article
- All-Atom Simulations Reveal the Effect of Membrane Composition on the Signaling of the NKG2A/CD94/HLA-E Immune Receptor Complex.Journal of chemical information and modeling · 2024Article
- Spontaneous Dimerization and Distinct Packing Modes of Transmembrane Domains in Receptor Tyrosine Kinases.Biochemistry · 2024Article
- Spontaneous Dimerization and Distinct Packing Modes of Transmembrane Domains in Receptor Tyrosine Kinases.bioRxiv : the preprint server for biology · 2024Article
- Machine Learning Derived Collective Variables for the Study of Protein Homodimerization in Membrane.Journal of chemical theory and computation · 2024Article
- Cholesterol and Lipid Rafts in the Biogenesis of Amyloid-β Protein and Alzheimer's Disease.Annual review of biophysics · 2024Review
- Nanodisc Reconstitution and Characterization of Amyloid-β Precursor Protein C99.Analytical chemistry · 2024Article
- Chimeric nanobody-decorated liposomes by self-assembly.Nature nanotechnology · 2024Article
- Nanodisc reconstitution and characterization of amyloid-β precursor protein C99.bioRxiv : the preprint server for biology · 2024Article
- Lipid environment modulates processivity and kinetics of a presenilin homolog acting on multiple substrates in vitro.The Journal of biological chemistry · 2023Article
- Elevated levels of sphingolipid MIPC in the plasma membrane disrupt the coordination of cell growth with cell wall formation in fission yeast.PLoS genetics · 2023Article
- Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol.Cell & bioscience · 2023Review
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
Cleavage of the amyloid precursor protein (APP) by γ-secretase is a crucial first step in the evolution of Alzheimer's disease. To discover the cleavage mechanism, it is urgent to predict the structures of APP monomers and dimers in varying membrane environments. We determined the structures of the C9923-55 monomer and homodimer as a function of membrane lipid composition using a multiscale simulation approach that blends atomistic and coarse-grained models. We demonstrate that the C9923-55 homodimer structures form a heterogeneous ensemble with multiple conformational states, each stabilized by characteristic interpeptide interactions. The relative probabilities of each conformational state are sensitive to the membrane environment, leading to substantial variation in homodimer peptide structure as a function of membrane lipid composition or the presence of an anionic lipid environment. In contrast, the helicity of the transmembrane domain of monomeric C991-55 is relatively insensitive to the membrane lipid composition, in agreement with experimental observations. The dimer structures of human EphA2 receptor depend on the lipid environment, which we show is linked to the location of the structural motifs in the dimer interface, thereby establishing that both sequence and membrane composition modulate the complete energy landscape of membrane-bound proteins. As a by-product of our work, we explain the discrepancy in structures predicted for C99 congener homodimers in membrane and micelle environments. Our study provides insight into the observed dependence of C99 protein cleavage by γ-secretase, critical to the formation of amyloid-β protein, on membrane thickness and lipid composition.
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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.