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Deciphering the Molecular Effects of Mutations on ATRX Cause ATRX Syndrome: A Molecular Dynamics Study. | LitMetric

Deciphering the Molecular Effects of Mutations on ATRX Cause ATRX Syndrome: A Molecular Dynamics Study.

J Cell Biochem

Department of Biotechnology, Bioinformatics Lab, School of Biosciences and Technology, VIT University, Vellore, 632014, Tamil Nadu, India.

Published: October 2017

AI Article Synopsis

  • * Molecular dynamics (MD) simulations revealed that both mutations caused significant changes in the protein's backbone dynamics, leading to structural distortions in specific α-helix regions, ultimately disrupting hydrogen bonds and local protein folding.
  • * Principal component analysis showed these mutants experienced differing conformational dynamics, making them structurally disordered and unable to perform the same functions as the wild type ADD domain, offering insights into how these mutations affect ATRX syndrome at a molecular level.

Article Abstract

α-thalassemia mental retardation X-linked (ATRX) syndrome is caused by the dysfunction of ATRFfigX protein. The present study explored the structural consequences influenced by two observed mutations V194I and C220R on ADD domain of ATRX protein by applying all atom molecular dynamics (MD) simulation. MD result showed that both the mutants exhibited wide variations in their backbone dynamics, as a result, mutant V210I showed complete distortion on α3 and the mutant C220R displayed a biased disruption on α2-3. The interference in the local folding of α-helices in both the mutants resulted by the loss of hydrogen bonds mediated by the backbone atoms. Principle component analysis (PCA) elucidated that both the mutants endured a diverse conformational dynamics, consequently adopted thermodynamically different conformational state. Besides, binding residues in both the mutants showed more structural disorder, thereby unable to recognize the hallmark modification, K9me3 (tri-methylated lysine at position 9) of histone H3 peptide and it was not conducive for the wild type ADD domain like functionality. Altogether, our findings provide knowledge to understand the structural and functional relationship of disease-associated mutations, V194I and C220R on ADD domain as well as gain further insights into the molecular pathogenesis of ATRX syndrome. J. Cell. Biochem. 118: 3318-3327, 2017. © 2017 Wiley Periodicals, Inc.

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Source
http://dx.doi.org/10.1002/jcb.25984DOI Listing

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