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Structural implications of H233L and H398P mutations in phospholipase Cζ: a full-atom molecular dynamics study on infertility-associated dysfunctions

dc.contributor.authorHinostroza, Fernando
dc.contributor.authorAlbornoz-Muñoz, Sofía
dc.contributor.authorVergara, Sebastián
dc.contributor.authorUrra, Gabriela
dc.contributor.authorAraya-Durán, Ingrid
dc.contributor.authorFissore, Rafael A.
dc.contributor.authorGonzález-Nilo, Fernando Danilo
dc.contributor.authorBustos, Daniel
dc.contributor.authorCarvacho, Ingrid
dc.date.accessioned2025-07-08T19:48:09Z
dc.date.available2025-07-08T19:48:09Z
dc.date.issued2025
dc.identifier.urihttp://repositorio.ucm.cl/handle/ucm/6235
dc.description.abstractPhospholipase Cζ (PLCζ), a sperm-specific enzyme, plays a critical role in mammalian fertilization. Mutations in PLCζ have been linked to male infertility, as they impair its ability to trigger calcium (Ca2+) oscillations necessary for egg activation and embryo development. During fertilization, PLCζ is introduced into the egg, where it hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate and diacylglycerol, leading to Ca2+ release from the endoplasmic reticulum. Human infertility-associated mutations include H233L, H398P, and R553P, which disrupt PLCζ function. To elucidate the molecular consequences of the mutations, we employed full-atom molecular dynamics simulations to analyze structural perturbations and their impact on PIP2 and Ca2+ binding. Our results reveal that H233L and H398P mutations significantly reduce interactions with PIP2, disrupting hydrogen bonding and salt bridge formation, leading to misalignment of the substrate. Additionally, these mutations destabilize Ca2+ binding by altering its positioning within the active site. In contrast, the R553P mutation primarily affects intramolecular stability and enzyme dynamics without impairing substrate or ion binding. Free energy calculations indicate an increased affinity for PIP2 in H233L and H398P mutants, leading to an aberrant substrate positioning and compromised hydrolysis. These structural insights help explain the egg activation failure and infertility of patients carrying these mutations.es_CL
dc.language.isoenes_CL
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 Chile*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/*
dc.sourceInternational Journal of Molecular Sciences, 26(10), 4706es_CL
dc.subjectPhospholipase Cζes_CL
dc.subjectPhosphatidylinositol 4,5-bisphosphatees_CL
dc.subjectInfertilityes_CL
dc.subjectH233L mutationes_CL
dc.subjectH398P mutationes_CL
dc.subjectR553P mutationes_CL
dc.titleStructural implications of H233L and H398P mutations in phospholipase Cζ: a full-atom molecular dynamics study on infertility-associated dysfunctionses_CL
dc.typeArticlees_CL
dc.ucm.facultadFacultad de Ciencias de la Saludes_CL
dc.ucm.indexacionScopuses_CL
dc.ucm.indexacionIsies_CL
dc.ucm.urimdpi.com/1422-0067/26/10/4706es_CL
dc.ucm.doidoi.org/10.3390/ijms26104706es_CL


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