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X-linked agammaglobulinemia (XLA) is a rare disease that affects the immune system, characterized by a serial development of bacterial infection from the onset of infantile age. Bruton tyrosine kinase (BTK) is a non-receptor cytoplasmic kinase that plays a crucial role in the B-lymphocyte maturation. The altered expression, mutation and/or structural variations of BTK are responsible for causing XLA. Here, we have performed extensive sequence and structure analyses of BTK to find deleterious variations and their pathogenic association with XLA. First, we screened the pathogenic variations in the BTK from a pool of publicly available resources, and their pathogenicity/tolerance and stability predictions were carried out. Finally, two pathogenic variations (E589G and M630K) were studied in detail and subjected to all-atom molecular dynamics simulation for 200 ns. Intramolecular hydrogen bonds (H-bonds), secondary structure, and principal component analysis revealed significant conformational changes in variants that support the structural basis of BTK dysfunction in XLA. The free energy landscape analysis revealed the presence of multiple energy minima, suggests that E589G brings a large destabilization and consequently unfolding behavior compared to M630K. Overall, our study suggests that amino acid substitutions, E589G, and M630K, significantly alter the structural conformation and stability of BTK. Copyright © 2020 Elsevier B.V. All rights reserved.

Citation

Taj Mohammad, Mohd Amir, Kartikay Prasad, Sagar Batra, Vijay Kumar, Afzal Hussain, Md Tabish Rehman, Mohamed F AlAjmi, Md Imtaiyaz Hassan. Impact of amino acid substitution in the kinase domain of Bruton tyrosine kinase and its association with X-linked agammaglobulinemia. International journal of biological macromolecules. 2020 Dec 01;164:2399-2408

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PMID: 32784026

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