Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature
| Autor: | Kasper Planeta Kepp, Ning Tang, Budheswar Dehury, Tom L. Blundell, Rukmankesh Mehra |
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| Přispěvatelé: | Mehra, Rukmankesh [0000-0001-6010-1514], Kepp, Kasper P [0000-0002-6754-7348], Apollo - University of Cambridge Repository |
| Rok vydání: | 2020 |
| Předmět: |
Aging
General Chemical Engineering Peptide Neurodegenerative Cleavage (embryo) Alzheimer's Disease Presenilin 03 medical and health sciences 0302 clinical medicine Amyloid precursor protein Acquired Cognitive Impairment Peptide bond 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology 34 Chemical Sciences Hydrogen bond Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) General Chemistry Brain Disorders Membrane chemistry Biophysics biology.protein Notch binding Dementia Generic health relevance 030217 neurology & neurosurgery |
| Zdroj: | Dehury, B, Tang, N, Mehra, R, Blundell, T L & Kepp, K P 2020, ' Side-by-side comparison of Notch-And C83 binding to γ-secretase in a complete membrane model at physiological temperature ', RSC Advances, vol. 10, no. 52, pp. 31215-31232 . https://doi.org/10.1039/d0ra04683c |
| ISSN: | 2046-2069 |
| DOI: | 10.1039/d0ra04683c |
| Popis: | γ-Secretase cleaves the C99 fragment of the amyloid precursor protein, leading to formation of aggregated β-amyloid peptide central to Alzheimer's disease, and Notch, essential for cell regulation. Recent cryogenic electron microscopy (cryo-EM) structures indicate major changes upon substrate binding, a β-sheet recognition motif, and a possible helix unwinding to expose peptide bonds towards nucleophilic attack. Here we report side-by-side comparison of the 303 K dynamics of the two proteins in realistic membranes using molecular dynamics simulations. Our ensembles agree with the cryo-EM data (full-protein Cα-RMSD = 1.62–2.19 A) but reveal distinct presenilin helix conformation states and thermal β-strand to coil transitions of C83 and Notch100. We identify distinct 303 K hydrogen bond dynamics and water accessibility of the catalytic sites. The RKRR motif (1758–1761) contributes significantly to Notch binding and serves as a “membrane anchor” that prevents Notch displacement. Water that transiently hydrogen bonds to G1753 and V1754 probably represents the catalytic nucleophile. At 303 K, Notch and C83 binding induce different conformation states, with Notch mostly present in a closed state with shorter Asp–Asp distance. This may explain the different outcome of Notch and C99 cleavage, as the latter is more imprecise with many products. Our identified conformation states may aid efforts to develop conformation-selective drugs that target C99 and Notch cleavage differently, e.g. Notch-sparing γ-secretase modulators. |
| Databáze: | OpenAIRE |
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