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Issue 52, 2020, Issue in Progress
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Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature

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Abstract

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 Å) 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.

Graphical abstract: Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature

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Supplementary files

Article information


Submitted
27 May 2020
Accepted
15 Aug 2020
First published
24 Aug 2020

This article is Open Access

RSC Adv., 2020,10, 31215-31232
Article type
Paper

Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature

B. Dehury, N. Tang, R. Mehra, T. L. Blundell and K. P. Kepp, RSC Adv., 2020, 10, 31215
DOI: 10.1039/D0RA04683C

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