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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
International Journal of Molecular Sciences, 24 (2023), 3; 1835. https://doi.org/10.3390/ijms24031835
Svedružić, Željko M.; Šendula Jengić, Vesna; Ostojić, Lucija

Institucijski repozitorij: Repozitorij Medicinskog fakulteta u Rijeci

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Svedružić, Ž. M., Šendula Jengić, V. i Ostojić, L. (2023). 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. International Journal of Molecular Sciences, 24. (3). doi: 10.3390/ijms24031835

Svedružić, Željko M., et al. "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." International Journal of Molecular Sciences, vol. 24, br. 3, 2023. https://doi.org/10.3390/ijms24031835

Svedružić, Željko M., Vesna Šendula Jengić i Lucija Ostojić. "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." International Journal of Molecular Sciences 24, br. 3 (2023). https://doi.org/10.3390/ijms24031835

Svedružić, Ž. M., Šendula Jengić, V. i Ostojić, L. (2023) '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', International Journal of Molecular Sciences, 24(3). doi: 10.3390/ijms24031835

Svedružić ŽM, Šendula Jengić V, Ostojić L. 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. International Journal of Molecular Sciences [Internet]. 17.01.2023. [pristupljeno 01.05.2024.];24(3). doi: 10.3390/ijms24031835

Ž. M. Svedružić, V. Šendula Jengić i L. Ostojić, "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", International Journal of Molecular Sciences, vol. 24, br. 3, Siječanj 2023. [Online]. Dostupno na: https://urn.nsk.hr/urn:nbn:hr:184:844075. [Citirano: 01.05.2024.]

Za citiranje koristite ovu mrežnu adresu: https://urn.nsk.hr/urn:nbn:hr:184:844075
Podaci o radu
Naslov (engleski)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
AutorŽeljko M. Svedružić
AutorVesna Šendula Jengić
AutorLucija Ostojić
Autorova ustanovaSveučilište u Rijeci
Medicinski fakultet
(Katedra za psihijatriju i psihološku medicinu)
Znanstveno / umjetničko
područje, polje i grana		BIOMEDICINA I ZDRAVSTVO
Kliničke medicinske znanosti
Psihijatrija
Sažetak (engleski)
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.
Ključne riječi (engleski)
Jezikengleski
Vrsta publikacijeZnanstveni rad - Izvorni znanstveni rad
Status objaveObjavljen
Vrsta recenzijeRecenziran - međunarodna recenzija
Verzija publikacijeObjavljena verzija rada (izdavačev PDF)
Naslov časopisaInternational Journal of Molecular Sciences
Brojčani podacivol. 24, br. 3, 1835
e-ISSN1422-0067
DOIhttps://doi.org/10.3390/ijms24031835
URN:NBNurn:nbn:hr:184:844075
Datum objave publikacije2023-01-17
URL dokumentahttps://www.mdpi.com/1422-0067/24/3/1835
Vrsta resursaTekst
Prava pristupaOtvoreni pristup
Uvjeti korištenjaIkona licence Imenovanje 4.0 međunarodna (CC BY 4.0)
Datum i vrijeme pohrane2023-01-26 13:52:13