RedOx regulation of LRRK2 kinase activity by active site cysteines

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dc.date.accessioned2024-09-02T10:37:52Z
dc.date.available2024-09-02T10:37:52Z
dc.date.issued2024-04-03
dc.description.sponsorshipGefördert im Rahmen des Projekts DEALger
dc.identifierdoi:10.17170/kobra-2024082910749
dc.identifier.urihttp://hdl.handle.net/123456789/16011
dc.language.isoeng
dc.relation.doidoi:10.1038/s41531-024-00683-5
dc.rightsNamensnennung 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectcomputational biology and bioinformaticseng
dc.subjectParkinson's diseaseeng
dc.subjectproteinseng
dc.subject.ddc540
dc.subject.ddc570
dc.subject.swdBioinformatikger
dc.subject.swdParkinson-Krankheitger
dc.subject.swdProteineger
dc.titleRedOx regulation of LRRK2 kinase activity by active site cysteineseng
dc.typeAufsatz
dc.type.versionpublishedVersion
dcterms.abstractMutations of the human leucine-rich repeat kinase 2 (LRRK2) have been associated with both, idiopathic and familial Parkinson’s disease (PD). Most of these pathogenic mutations are located in the kinase domain (KD) or GTPase domain of LRRK2. In this study we describe a mechanism in which protein kinase activity can be modulated by reversible oxidation or reduction, involving a unique pair of adjacent cysteines, the “CC” motif. Among all human protein kinases, only LRRK2 contains this “CC” motif (C2024 and C2025) in the Activation Segment (AS) of the kinase domain. In an approach combining site-directed mutagenesis, biochemical analyses, cell-based assays, and Gaussian accelerated Molecular Dynamics (GaMD) simulations we could attribute a role for each of those cysteines. We employed reducing and oxidizing agents with potential clinical relevance to investigate effects on kinase activity and microtubule docking. We find that each cysteine gives a distinct contribution: the first cysteine, C2024, is essential for LRRK2 protein kinase activity, while the adjacent cysteine, C2025, contributes significantly to redox sensitivity. Implementing thiolates (R-S-) in GaMD simulations allowed us to analyse how each of the cysteines in the “CC” motif interacts with its surrounding residues depending on its oxidation state. From our studies we conclude that oxidizing agents can downregulate kinase activity of hyperactive LRRK2 PD mutations and may provide promising tools for therapeutic strategies.eng
dcterms.accessRightsopen access
dcterms.creatorTrilling, Chiara R.
dcterms.creatorWeng, Jui-Hung
dcterms.creatorKaila Sharma, Pallavi
dcterms.creatorNolte, Viktoria
dcterms.creatorWu, Jian
dcterms.creatorMa, Wen
dcterms.creatorBoassa, Daniela
dcterms.creatorTaylor, Susan T.
dcterms.creatorHerberg, Friedrich Wilhelm
dcterms.source.articlenumber75
dcterms.source.identifiereissn:2373-8057
dcterms.source.journalnpj Parkinson's Diseaseeng
dcterms.source.volumeVolume 10
kup.iskupfalse

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