Hydrophobicity-Driven Disruption Mechanism in Kindlin-3 Induced by Leukocyte Adhesion Deficiency Mutation

Leukocyte adhesion deficiency type III (LAD-III) is caused by amino acid mutations in Kindlin-3, which result in integrin activation defects. The QW motif in the Kindlin family is particularly important for integrin activation, and the Q595P mutation in the QW motif of Kindlin-3 leads to LAD-III. However, the molecular mechanisms underlying this disruption remain unclear. In this study, we employed molecular dynamics (MD) and steered MD simulations to investigate how the pathogenic Q595P mutation in Kindlin-3 alters its interaction with β1-integrin under physiological conditions. Our results show that the Q595P mutation induces conformational changes in neighboring residues, leading to a reduction in binding affinity, specificity, and mechanical strength, primarily driven by hydrophobic changes. Specifically, the Q595P mutation disrupts the torsional dynamics of residues at the Kindlin-3 binding interface by disturbing the hydrophobic environment, weakening the hydrogen bonds that are essential for stabilizing the Kindlin-3/β1-integrin interaction under both forceful and nonforceful conditions. Additionally, it enhances nonspecific hydrophobic interactions on nonbinding surfaces, further destabilizing the overall binding. These findings provide important insights into the molecular mechanisms by which pathogenic mutations in conserved regions of Kindlin-3 lead to integrin activation defects and contribute to the pathogenesis of LAD-III.