M630L MUTATION DISRUPTS THE STRUCTURE CONFORMATION OF BRUTON TYROSINE KINASE (BTK) DOMAIN IN PATIENT WITH X-LINKED AGAMMAGLOBULINEMIA: INSIGHTS FROM IN SILICO
DOI:
https://doi.org/10.11113/jurnalteknologi.v87.22318Keywords:
X-linked Agammaglobulinemia (XLA); Bruton Tyrosine Kinase (BTK); Non-synonymous Single Nucleotide Polymorphism (nsSNP); Molecular Dynamics (MD) simulation; Cluster analysis; Principle Component Analysis (PCA)Abstract
X-Linked Agammaglobulinemia (XLA) is a rare inherited disease, attributed to mutations found in the Bruton Tyrosine Kinase (BTK) gene. This research outlines the application of Molecular Modelling and Simulation to predict the effects of a novel non-synonymous Single Nucleotide Polymorphism (nsSNP) reported in the BTK kinase domain protein of a male XLA patient. The mutation at position c.1888A>T causes a substitution of p.M630L within the kinase domain of the BTK protein. Functional assessment using in silico prediction tools (SIFT, Polyphen-2, PROVEAN, MutationAssessor, PANTHER, FATHMM, MutPred and MutationTaster) predicted the mutation to be deleterious, potentially disrupting both the structure and function of the protein. Nevertheless, the mutation is not located at the active site of the kinase domain. Consequently, the molecular dynamics (MD) simulations were performed to investigate the impact of amino acid substitution to the three-dimensional (3D) conformational structure of the BTK protein, contributing to the disease phenotype observed in the reported patient. MD analysis, clustering analysis and Principle Component Analysis (PCA) revealed that the 3D conformational structure of the kinase domain of mutant protein to be more compact and rigid compared to the wildtype. Given that the alterations in protein structure can influence their functional characteristics, the p.M630L mutation within the BTK protein kinase domain might disrupt the protein function, potentially impeding the maturation of B cells and contributing to the onset of XLA disease.
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