Structural characterization of disease-causing mutations on SAP and the functional impact on the SLAM peptide: a molecular dynamics approach

Abstract

X-linked lymphoproliferative (XLP) syndrome is an extremely rare inherited immunodeficiency disease characterized by severe immune dysregulation caused by mutations in signaling lymphocyte activation molecule (SLAM) associated protein (SAP) gene. The XLP syndrome was manifested due to dysfunction of SAP as a result of amino acid substitution. Hence, to understand the molecular aspects of the XLP syndrome, we structurally characterized two observed mutations, R32Q and T53I on SAP through the systematic molecular dynamics (MD) approach. Our MD analysis showed that mutant structures elucidated an atomic level variation influenced by mutations that substantially altered the residual flexibility and more importantly the hot spot residues as well in unbound and bound systems. In addition, change in residual flexibility of mutant structures showed an unusual conformational behavior associated with their molecular recognition function compared to the wild-type SAP in both systems. Besides, both mutant structures established different secondary structural profiles during the course of the simulation period in both systems. Moreover, the docking analysis revealed that mutant R32Q and T53I structures displayed remarkably reduced levels of binding affinity to the unphosphorylated SLAM peptide with respect to their docking scores. Collectively, our findings provide knowledge to understand the structural and functional relationship of disease-causing mutations, R32Q and T53I on SAP as well as gain further insights into the molecular pathogenesis of the XLP syndrome.