ArticleBiophysical journal2014
Side-chain to main-chain hydrogen bonding controls the intrinsic backbone dynamics of the amyloid precursor protein transmembrane helix.
Article in Biophysical journal, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 35 citations in OpenAlex.
- Conformational Flexibility of Transmembrane Helices: How it Works and Where it Matters.Chemical reviews · 2026Review
- Cooperation of N- and C-terminal substrate transmembrane domain segments in intramembrane proteolysis by γ-secretase.Communications biology · 2023Article
- Non-canonical Shedding of TNFα by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix.iScience · 2020Article
- γ-Secretase cleavage of the Alzheimer risk factor TREM2 is determined by its intrinsic structural dynamics.The EMBO journal · 2020Article
- Bicelles Rich in both Sphingolipids and Cholesterol and Their Use in Studies of Membrane Proteins.Journal of the American Chemical Society · 2020Article
- Substrate-Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype.Frontiers in molecular neuroscience · 2020Review
- Modulating Hinge Flexibility in the APP Transmembrane Domain Alters γ-Secretase Cleavage.Biophysical journal · 2019Article
- Increased H-Bond Stability Relates to Altered ε-Cleavage Efficiency and Aβ Levels in the I45T Familial Alzheimer's Disease Mutant of APP.Scientific reports · 2019Article
- 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
- Article
- Intramembrane proteolysis of β-amyloid precursor protein by γ-secretase is an unusually slow process.Biophysical journal · 2015Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Many transmembrane helices contain serine and/or threonine residues whose side chains form intrahelical H-bonds with upstream carbonyl oxygens. Here, we investigated the impact of threonine side-chain/main-chain backbonding on the backbone dynamics of the amyloid precursor protein transmembrane helix. This helix consists of a N-terminal dimerization region and a C-terminal cleavage region, which is processed by γ-secretase to a series of products. Threonine mutations within this transmembrane helix are known to alter the cleavage pattern, which can lead to early-onset Alzheimer's disease. Circular dichroism spectroscopy and amide exchange experiments of synthetic transmembrane domain peptides reveal that mutating threonine enhances the flexibility of this helix. Molecular dynamics simulations show that the mutations reduce intrahelical amide H-bonding and H-bond lifetimes. In addition, the removal of side-chain/main-chain backbonding distorts the helix, which alters bending and rotation at a diglycine hinge connecting the dimerization and cleavage regions. We propose that the backbone dynamics of the substrate profoundly affects the way by which the substrate is presented to the catalytic site within the enzyme. Changing this conformational flexibility may thus change the pattern of proteolytic processing.
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