Computational study of the activation mechanism of wild-type parkin and its clinically relevant mutant

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dc.contributor.authorCinviz, Zeynep Nur
dc.contributor.authorŞensoy, Özge
dc.date.accessioned2026-04-15T10:29:28Z
dc.date.available2026-04-15T10:29:28Z
dc.date.issued2025
dc.departmentİstanbul Medipol Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Bilgisayar Mühendisliği Bölümü
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü
dc.description.abstractParkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It impairs the control of movement and balance. Parkin mutations worsen the symptoms in sporadic cases and cause the early onset of the disease. Therefore, recent efforts have focused on the rescue of defective parkin by engineered proteins or small-molecule activators to enhance parkin activation. These attempts require holistic understanding of the multistep activation mechanism and molecular effects of disease-associated mutations. Hereby, we provided a comprehensive analysis of the activation mechanism of parkin and a clinically relevant mutant, parkinS167N, using molecular dynamics simulations based on the following crystal structures: (1) parkin, (2) parkin/pUb (phosphorylated Ubiquitin), (3) pparkin/pUb, and (4) pparkin/pUb/UbcH7-Ub. Each of these represents an individual step in the activation process. We showed that the mutation impacted the dynamics of not only the RING0 domain, where it is localized, but also the RING2, Ubl, and IBR domains. We identified residues participating in the allosteric interaction network involved in parkin activation. Some of them are mutated in PD-associated parkin variants. The RING0 domain provides a binding interface with various proteins, so understanding problems associated with the mutation paves the way to the discovery of effective engineered proteins or small molecules that activate mutant parkin.
dc.description.sponsorshipTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK)
dc.identifier.citationCinviz, Z. N. ve Şensoy, Ö. (2025). Computational study of the activation mechanism of wild-type parkin and its clinically relevant mutant. ACS Chemical Neuroscience, 16(3), 417-427. http://dx.doi.org/10.1021/acschemneuro.4c00630
dc.identifier.doi10.1021/acschemneuro.4c00630
dc.identifier.endpage427
dc.identifier.issn1948-7193
dc.identifier.issue3
dc.identifier.pmid39865619
dc.identifier.scopus2-s2.0-85216305936
dc.identifier.scopusqualityQ1
dc.identifier.startpage417
dc.identifier.urihttp://dx.doi.org/10.1021/acschemneuro.4c00630
dc.identifier.urihttps://hdl.handle.net/20.500.12511/13425
dc.identifier.volume16
dc.identifier.wosWOS:001408428500001
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorCinviz, Zeynep Nur
dc.institutionauthorŞensoy, Özge
dc.institutionauthorid0000-0001-5950-3436
dc.language.isoen
dc.relation.ispartofACS Chemical Neuroscience
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.relation.tubitakinfo:eu-repo/grantAgreement/TUBITAK/1919B012002278
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectMitophagy
dc.subjectMolecular Dynamics
dc.subjectParkin Mutation
dc.subjectParkinson's Disease
dc.subjectRING0 Domain
dc.titleComputational study of the activation mechanism of wild-type parkin and its clinically relevant mutant
dc.typeArticle

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