9z00

Kindlin-3/Integrin Beta3 Cytoplasmic Tail Complex

spinqualitylabelsall models 9z00, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9z00 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.1992168Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease URP2_HUMAN Leukocyte adhesion deficiency type III. The disease is caused by mutations affecting the gene represented in this entry. Function URP2_HUMAN Plays a central role in cell adhesion in hematopoietic cells. Acts by activating the integrin beta-1-3 (ITGB1, ITGB2 and ITGB3). Required for integrin-mediated platelet adhesion and leukocyte adhesion to endothelial cells. Required for activation of integrin beta-2 (ITGB2) in polymorphonuclear granulocytes (PMNs) (By similarity). Isoform 2 may act as a repressor of NF-kappa-B and apoptosis. Publication Abstract from PubMed BACKGROUND: Leukocyte 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 essential integrin co-activator that binds to the cytoplasmic tails (CTs) of integrin beta 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 seven missense variants that localize to the FERM domain, specifically within the F1 (L102P, E138K, W229C, K252N), F2 (L274R), and F3 (L574P, Q595P) subdomains. OBJECTIVES: To define the structural mechanisms underlying LAD-III-associated missense variants in kindlin-3. PATIENTS/METHODS: Structural and biochemical approaches, including X-ray crystallography, were employed. RESULTS: All seven missense variants markedly reduced kindlin-3 expression, consistent with destabilization of intra- and inter-subdomain interactions within the FERM domain. We determined the crystal structures of the kindlin-3 FERM domain in complex with integrin beta2 and beta3 CT peptides. These structures reveal that Q595, although not directly contacting the beta CTs, is centrally positioned within the F3 subdomain between two adjacent interaction sites critical for beta 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. CONCLUSIONS: Our 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. Structural basis of kindlin-3 in leukocyte adhesion deficiency III.,Xu Z, Ma S, Zhou Y, Ma YQ J Thromb Haemost. 2026 Jun 26:S1538-7836(26)00406-X. doi: , 10.1016/j.jtha.2026.06.021. PMID:42362029 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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