Matches in SemOpenAlex for { <https://semopenalex.org/work/W4317036349> ?p ?o ?g. }
- W4317036349 endingPage "1835" @default.
- W4317036349 startingPage "1835" @default.
- W4317036349 abstract "Pathogenic changes in γ-secretase activity, along with its response to different drugs, can be affected by changes in the saturation of γ-secretase with its substrate. We analyze the saturation of γ-secretase with its substrate using multiscale molecular dynamics studies. We found that an increase in the saturation of γ-secretase with its substrate could result in the parallel binding of different substrate molecules at the docking site and the active site. The C-terminal domain of the substrate bound at the docking site can interact with the most dynamic presenilin sites at the cytosolic end of the active site tunnel. Such interactions can inhibit the ongoing catalytic activity and increase the production of the longer, more hydrophobic, and more toxic Aβ proteins. Similar disruptions in dynamic presenilin structures can be observed with different drugs and disease-causing mutations. Both, C99-βCTF-APP substrate and its different Aβ products, can support the toxic aggregation. The aggregation depends on the substrate N-terminal domain. Thus, the C99-βCTF-APP substrate and β-secretase path can be more toxic than the C83-αCTF-APP substrate and α-secretase path. Nicastrin can control the toxic aggregation in the closed conformation. The binding of the C99-βCTF-APP substrate to γ-secretase can be controlled by substrate channeling between the nicastrin and β-secretase. We conclude that the presented two-substrate mechanism could explain the pathogenic changes in γ-secretase activity and Aβ metabolism in different sporadic and familial cases of Alzheimer's disease. Future drug-development efforts should target different cellular mechanisms that regulate the optimal balance between γ-secretase activity and amyloid metabolism." @default.
- W4317036349 created "2023-01-18" @default.
- W4317036349 creator A5033170495 @default.
- W4317036349 creator A5065973339 @default.
- W4317036349 creator A5090159561 @default.
- W4317036349 date "2023-01-17" @default.
- W4317036349 modified "2023-09-25" @default.
- W4317036349 title "The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer’s Disease" @default.
- W4317036349 cites W1501971533 @default.
- W4317036349 cites W1530704185 @default.
- W4317036349 cites W1541002730 @default.
- W4317036349 cites W1557800628 @default.
- W4317036349 cites W1607931568 @default.
- W4317036349 cites W1633528255 @default.
- W4317036349 cites W1890431460 @default.
- W4317036349 cites W1963904512 @default.
- W4317036349 cites W1969271586 @default.
- W4317036349 cites W1971572968 @default.
- W4317036349 cites W1974864309 @default.
- W4317036349 cites W1978281908 @default.
- W4317036349 cites W1985115020 @default.
- W4317036349 cites W1986892064 @default.
- W4317036349 cites W1987888225 @default.
- W4317036349 cites W1998358793 @default.
- W4317036349 cites W2005926152 @default.
- W4317036349 cites W2008802647 @default.
- W4317036349 cites W2008988975 @default.
- W4317036349 cites W2013843163 @default.
- W4317036349 cites W2016447615 @default.
- W4317036349 cites W2020089910 @default.
- W4317036349 cites W2026596383 @default.
- W4317036349 cites W2029667189 @default.
- W4317036349 cites W2033067082 @default.
- W4317036349 cites W2035345772 @default.
- W4317036349 cites W2035612133 @default.
- W4317036349 cites W2041601288 @default.
- W4317036349 cites W2043383967 @default.
- W4317036349 cites W2046610378 @default.
- W4317036349 cites W2049451196 @default.
- W4317036349 cites W2050586736 @default.
- W4317036349 cites W2059008719 @default.
- W4317036349 cites W2060802768 @default.
- W4317036349 cites W2061123524 @default.
- W4317036349 cites W2076868543 @default.
- W4317036349 cites W2077225773 @default.
- W4317036349 cites W2077813961 @default.
- W4317036349 cites W2085989411 @default.
- W4317036349 cites W2092508662 @default.
- W4317036349 cites W2097750046 @default.
- W4317036349 cites W2106753168 @default.
- W4317036349 cites W2114926230 @default.
- W4317036349 cites W2118346288 @default.
- W4317036349 cites W2120396539 @default.
- W4317036349 cites W2121634426 @default.
- W4317036349 cites W2128084592 @default.
- W4317036349 cites W2132629607 @default.
- W4317036349 cites W2135990814 @default.
- W4317036349 cites W2140831051 @default.
- W4317036349 cites W2140900586 @default.
- W4317036349 cites W2141205833 @default.
- W4317036349 cites W2145936899 @default.
- W4317036349 cites W2152997175 @default.
- W4317036349 cites W2153878026 @default.
- W4317036349 cites W2154556865 @default.
- W4317036349 cites W2154755614 @default.
- W4317036349 cites W2160327181 @default.
- W4317036349 cites W2163790333 @default.
- W4317036349 cites W2167099782 @default.
- W4317036349 cites W2168879529 @default.
- W4317036349 cites W2171268876 @default.
- W4317036349 cites W2206954826 @default.
- W4317036349 cites W2232972230 @default.
- W4317036349 cites W2344407798 @default.
- W4317036349 cites W2460255279 @default.
- W4317036349 cites W2549974199 @default.
- W4317036349 cites W2558085896 @default.
- W4317036349 cites W2596899328 @default.
- W4317036349 cites W2623998317 @default.
- W4317036349 cites W2734651019 @default.
- W4317036349 cites W2742157915 @default.
- W4317036349 cites W2765342165 @default.
- W4317036349 cites W2777007947 @default.
- W4317036349 cites W2803024172 @default.
- W4317036349 cites W2883126887 @default.
- W4317036349 cites W2893189760 @default.
- W4317036349 cites W2896511009 @default.
- W4317036349 cites W2898713357 @default.
- W4317036349 cites W2905232362 @default.
- W4317036349 cites W2908723002 @default.
- W4317036349 cites W2909479706 @default.
- W4317036349 cites W2923472323 @default.
- W4317036349 cites W2936852185 @default.
- W4317036349 cites W2950875286 @default.
- W4317036349 cites W2989795769 @default.
- W4317036349 cites W3003425964 @default.
- W4317036349 cites W3025755767 @default.
- W4317036349 cites W3037461680 @default.
- W4317036349 cites W3082942379 @default.