ArticleJournal of thrombosis and haemostasis : JTH2026
Structural basis of kindlin-3 in leukocyte adhesion deficiency III.
Article in Journal of thrombosis and haemostasis : JTH, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundLeukocyte adhesion deficiency III (LAD-III) is caused by impaired integrin activation in hematopoietic cells due to mutations in FERMT3, which encodes kindlin-3, an FERM domain-containing adaptor, and is an essential integrin coactivator that binds to the cytoplasmic tails (CTs) of integrin β subunits. Defective kindlin-3 impairs integrin activation in both leukocytes and platelets, leading to recurrent infections and severe bleeding. More than 30 pathogenic FERMT3 mutations have been identified, including 7 missense variants that localize to the FERM domain, specifically within the F1 (L102P, E138K, W229C, and K252N), F2 (L274R), and F3 (L574P and Q595P) subdomains.
objectivesThis study aimed to define the structural mechanisms underlying LAD-III-associated missense variants in kindlin-3.
methodsStructural and biochemical approaches, including X-ray crystallography, were employed.
resultsAll 7 missense variants markedly reduced kindlin-3 expression, consistent with the destabilization of intra- and intersubdomain interactions within the FERM domain. We determined the crystal structures of the kindlin-3 FERM domain in complex with integrin β2 and β3 CT peptides. These structures reveal that Q595, although not directly contacting the β CTs, is centrally positioned within the F3 subdomain between 2 adjacent interaction sites critical for β CT binding. The Q595P substitution introduces a conformational constraint that disrupts coordination between these binding sites, thereby weakening kindlin-3-integrin interactions and impairing integrin activation.
conclusionOur findings provide a structural framework for understanding LAD-III-associated kindlin-3 missense mutations and underscore the critical role of FERM domain integrity in kindlin-3-mediated integrin activation.
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