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Scientific paper - Original scientific paper
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

Institutional repository: Repository of the University of Rijeka, Faculty of Medicine

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Svedružić, Ž. M., Šendula Jengić, V. & 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, no. 3, 2023. https://doi.org/10.3390/ijms24031835

Svedružić, Željko M., Vesna Šendula Jengić and 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, no. 3 (2023). https://doi.org/10.3390/ijms24031835

Svedružić, Ž. M., Šendula Jengić, V. and 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]. 2023 January 17 [cited 2024 April 27];24(3). doi: 10.3390/ijms24031835

Ž. M. Svedružić, V. Šendula Jengić and 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, no. 3, January 2023. [Online]. Available at: https://urn.nsk.hr/urn:nbn:hr:184:844075. [Accessed: 27 April 2024]

Metadata
Title (english)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
AuthorŽeljko M. Svedružić
AuthorVesna Šendula Jengić
AuthorLucija Ostojić
Author's institutionUniversity of Rijeka
Faculty of Medicine
(Department of Psychiatry and Psychological Medicine)
Scientific / art field,
discipline and subdiscipline		BIOMEDICINE AND HEALTHCARE
Clinical Medical Sciences
Psychiatry
Abstract (english)
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.
Keywords (english)
Languageenglish
Publication typeScientific paper - Original scientific paper
Publication statusPublished
Peer reviewPeer review - international
Publication versionPublished version
Journal titleInternational Journal of Molecular Sciences
Numberingvol. 24, no. 3, 1835
e-ISSN1422-0067
DOIhttps://doi.org/10.3390/ijms24031835
URN:NBNurn:nbn:hr:184:844075
Publication2023-01-17
Document URLhttps://www.mdpi.com/1422-0067/24/3/1835
Type of resourceText
Access conditionsOpen access
Terms of useLicence Attribution 4.0 International (CC BY 4.0) icon
Created on2023-01-26 13:52:13