Unraveling the Role of the Tyrosine Tetrad from the Binding Site of the Epigenetic Writer MLL3 in the Catalytic Mechanism and Methylation Multiplicity

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dc.contributor.authorBlanco Esperguez, Kevin
dc.contributor.authorTuñón, Iñaki
dc.contributor.authorKästner, Johannes
dc.contributor.authorMendizábal, Fernando
dc.contributor.authorMiranda Rojas, Sebastián
dc.date.accessioned2023-08-29T20:23:53Z
dc.date.available2023-08-29T20:23:53Z
dc.date.issued2022-09
dc.descriptionIndexación: Scopus.es
dc.description.abstractMLL3, also known as KMT2C, is a lysine mono-methyltransferase in charge of the writing of an epigenetic mark on lysine 4 from histone 3. The catalytic site of MLL3 is composed of four tyrosines, namely, Y44, Y69, Y128, and Y130. Tyrosine residues are highly conserved among lysine methyltransferases’ catalytic sites, although their complete function is still unclear. The exploration of how modifications on these residues from the enzymatic machinery impact the enzymatic activity of MLL3 could shed light transversally into the inner functioning of enzymes with similar characteristics. Through the use of QMMM calculations, we focus on the effect of the mutation of each tyrosine from the catalytic site on the enzymatic activity and the product specificity in the current study. While we found that the mutations of Y44 and Y128 by phenylalanine inactivated the enzyme, the mutation of Y128 by alanine reactivated the enzymatic activity of MLL3. Moreover, according to our models, the Y128A mutant was even found to be capable of di- and tri-methylate lysine 4 from histone 3, what would represent a gain of function mutation, and could be responsible for the development of diseases. Finally, we were able to establish the inactivation mechanism, which involved the use of Y130 as a water occlusion structure, whose conformation, once perturbed by its mutation or Y128 mutant, allows the access of water molecules that sequester the electron pair from lysine 4 avoiding its methylation process and, thus, increasing the barrier height. © 2022 by the authors.es
dc.description.urihttps://www.mdpi.com/1422-0067/23/18/10339
dc.identifier.citationInternational Journal of Molecular Sciences, Volume 23, Issue 18, September 2022, Article number 10339es
dc.identifier.doi10.3390/ijms231810339
dc.identifier.issn1661-6596
dc.identifier.urihttps://repositorio.unab.cl/xmlui/handle/ria/52911
dc.language.isoenes
dc.publisherMDPIes
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCanceres
dc.subjectEnzyme catalysises
dc.subjectEpigeneticses
dc.subjectMutantses
dc.subjectProduct specificityes
dc.subjectQM/MMes
dc.titleUnraveling the Role of the Tyrosine Tetrad from the Binding Site of the Epigenetic Writer MLL3 in the Catalytic Mechanism and Methylation Multiplicityes
dc.typeArtículoes
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