Abstract
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.
•Bruton tyrosine kinase (BTK) plays a vital role in oncogenic signaling, its defective function or mutation causes primary immunodeficiency XLA.•We extensively studied the effect of amino acid substitution on the structure and function of BTK using state-of-the-art bioinformatics methods including MD simulation.•Two important substitutions (E589G and M630K) identified which were responsible for alteration in the structural conformation and stability of BTK.•E589G substitution causes pronounced alteration in the conformation and dynamic stability of BTK compared to M630K.•This study provides the molecular basis of the cause of XLA mediated by certain amino acid substitutions in BTK.