Molecular dynamics of C99-bound {gamma}-secretase reveal two binding modes with distinct compactness, stability, and active-site retention: implications for A{beta} production

We report here an essentially complete atomic model of C99 within wild-type -secretase that respects all the experimental constraints and additionally describes loop, helix, and C99 substrate dynamics in a realistic all-atom membrane. Our model represents the matured auto-cleaved state required for catalysis. From two independent 500-ns molecular dynamic simulations, we identify two conformation states of C99 in equilibrium, a compact and a loose state. Our simulations provide a basis for C99 processing and Aβ formation and explain the production of longer and shorter Aβ, as the compact state retains C99 for longer and thus probably trims to shorter Aβ peptides. We expect pathogenic presenilin mutations to stabilize the loose over the compact state. The simulations detail the role of the Lys53–Lys54–Lys55 anchor for C99 binding, a loss of helicity of bound C99, and positioning of Thr48 and Leu49 leading to alternative trimming pathways on opposite sides of the C99 helix in three amino acid steps. The C99 binding topology resembles that of C83-bound -secretase without membrane but lacks a presenilin 1-C99 β-sheet, which could be induced by C83's stronger binding. The loose state should be selectively disfavored by -secretase modulators to increase C99 trimming and reduce the formation of longer Aβ, a strategy that is currently much explored but has lacked a structural basis.
Source: Biochemical Journal - Category: Biochemistry Authors: Tags: Research Articles Source Type: research

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Abstract Identification of tyrosine Fyn kinase inhibitor is recognized as an effective and feasible therapeutic measure in reducing consequences of memory loss disorder Alzheimer's. The present investigation has been attempted with an objective to find out a novel potent inhibitor with similar homological structure to Fyn kinase using structure based in silico screening measure. Such derived structure was compared with natural data base pool and were systematically analyzed. Ligand based interaction was also tested and evaluated. We applied a molecular dynamic simulation technique to validate the stability of the ...
Source: Bioinformation - Category: Bioinformatics Authors: Tags: Bioinformation Source Type: research
Authors: Lu X, Yang B, Yu H, Hu X, Nie J, Wan B, Zhang M, Lü C Abstract Context: Neuroligin-1 (NLGN1) is a cell adhesion protein located on the excitatory postsynaptic membrane. β-Amyloid (Aβ)-induced neuroinflammation decreases NLGN1 expression through epigenetic mechanisms. Triptolide (T10) and tripchlorolide (T4) exert protective effects on synapses in Alzheimer's disease (AD) mice, but the mechanisms remain unclear. Objective: The effects of T10 and T4 on hippocampal NLGN1 expression in AD mice and the epigenetic mechanisms were assessed using chromatin immunoprecipitation and methylated DNA immu...
Source: Pharmaceutical Biology - Category: Drugs & Pharmacology Tags: Pharm Biol Source Type: research
Publication date: July 2019Source: Alzheimer's &Dementia, Volume 15, Issue 7Author(s): Zaven S. Khachaturian, Lewis H. Kuller, Ara S. Khachaturian
Source: Alzheimer's and Dementia: The Journal of the Alzheimer's Association - Category: Geriatrics Source Type: research
This article summarizes the evidence for translation into action.
Source: Alzheimer's and Dementia: The Journal of the Alzheimer's Association - Category: Geriatrics Source Type: research
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Source: Alzheimer's and Dementia: The Journal of the Alzheimer's Association - Category: Geriatrics Source Type: research
Publication date: July 2019Source: Alzheimer's &Dementia, Volume 15, Issue 7Author(s):
Source: Alzheimer's and Dementia: The Journal of the Alzheimer's Association - Category: Geriatrics Source Type: research
Publication date: July 2019Source: Alzheimer's &Dementia, Volume 15, Issue 7Author(s):
Source: Alzheimer's and Dementia: The Journal of the Alzheimer's Association - Category: Geriatrics Source Type: research
Publication date: July 2019Source: Alzheimer's &Dementia, Volume 15, Issue 7Author(s):
Source: Alzheimer's and Dementia: The Journal of the Alzheimer's Association - Category: Geriatrics Source Type: research
Publication date: July 2019Source: Alzheimer's &Dementia, Volume 15, Issue 7Author(s):
Source: Alzheimer's and Dementia: The Journal of the Alzheimer's Association - Category: Geriatrics Source Type: research
Publication date: July 2019Source: Alzheimer's &Dementia, Volume 15, Issue 7Author(s):
Source: Alzheimer's and Dementia: The Journal of the Alzheimer's Association - Category: Geriatrics Source Type: research
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