| Structural highlights
Disease
URP2_HUMAN Leukocyte adhesion deficiency type III. The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] [5]
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).[6] [7] [8] [9] Isoform 2 may act as a repressor of NF-kappa-B and apoptosis.[10] [11] [12] [13]
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[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kuijpers TW, van de Vijver E, Weterman MA, de Boer M, Tool AT, van den Berg TK, Moser M, Jakobs ME, Seeger K, Sanal O, Unal S, Cetin M, Roos D, Verhoeven AJ, Baas F. LAD-1/variant syndrome is caused by mutations in FERMT3. Blood. 2009 May 7;113(19):4740-6. doi: 10.1182/blood-2008-10-182154. Epub 2008, Dec 8. PMID:19064721 doi:https://dx.doi.org/10.1182/blood-2008-10-182154
- ↑ Svensson L, Howarth K, McDowall A, Patzak I, Evans R, Ussar S, Moser M, Metin A, Fried M, Tomlinson I, Hogg N. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med. 2009 Mar;15(3):306-12. doi: 10.1038/nm.1931. Epub 2009 Feb 22. PMID:19234463 doi:https://dx.doi.org/10.1038/nm.1931
- ↑ Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma YQ, Podrez EA, Tosi M, Lennon DP, Caplan AI, Shurin SB, Plow EF, Byzova TV. A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med. 2009 Mar;15(3):313-8. doi: 10.1038/nm.1917. Epub 2009 Feb 22. PMID:19234460 doi:https://dx.doi.org/10.1038/nm.1917
- ↑ Mory A, Feigelson SW, Yarali N, Kilic SS, Bayhan GI, Gershoni-Baruch R, Etzioni A, Alon R. Kindlin-3: a new gene involved in the pathogenesis of LAD-III. Blood. 2008 Sep 15;112(6):2591. doi: 10.1182/blood-2008-06-163162. PMID:18779414 doi:https://dx.doi.org/10.1182/blood-2008-06-163162
- ↑ Manevich-Mendelson E, Feigelson SW, Pasvolsky R, Aker M, Grabovsky V, Shulman Z, Kilic SS, Rosenthal-Allieri MA, Ben-Dor S, Mory A, Bernard A, Moser M, Etzioni A, Alon R. Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4 adhesiveness developed under shear flow conditions. Blood. 2009 Sep 10;114(11):2344-53. doi: 10.1182/blood-2009-04-218636. Epub 2009 , Jul 17. PMID:19617577 doi:https://dx.doi.org/10.1182/blood-2009-04-218636
- ↑ Wang L, Deng W, Shi T, Ma D. URP2SF, a FERM and PH domain containing protein, regulates NF-kappaB and apoptosis. Biochem Biophys Res Commun. 2008 Apr 18;368(4):899-906. doi:, 10.1016/j.bbrc.2008.02.024. Epub 2008 Feb 14. PMID:18280249 doi:https://dx.doi.org/10.1016/j.bbrc.2008.02.024
- ↑ Kuijpers TW, van de Vijver E, Weterman MA, de Boer M, Tool AT, van den Berg TK, Moser M, Jakobs ME, Seeger K, Sanal O, Unal S, Cetin M, Roos D, Verhoeven AJ, Baas F. LAD-1/variant syndrome is caused by mutations in FERMT3. Blood. 2009 May 7;113(19):4740-6. doi: 10.1182/blood-2008-10-182154. Epub 2008, Dec 8. PMID:19064721 doi:https://dx.doi.org/10.1182/blood-2008-10-182154
- ↑ Svensson L, Howarth K, McDowall A, Patzak I, Evans R, Ussar S, Moser M, Metin A, Fried M, Tomlinson I, Hogg N. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med. 2009 Mar;15(3):306-12. doi: 10.1038/nm.1931. Epub 2009 Feb 22. PMID:19234463 doi:https://dx.doi.org/10.1038/nm.1931
- ↑ Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma YQ, Podrez EA, Tosi M, Lennon DP, Caplan AI, Shurin SB, Plow EF, Byzova TV. A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med. 2009 Mar;15(3):313-8. doi: 10.1038/nm.1917. Epub 2009 Feb 22. PMID:19234460 doi:https://dx.doi.org/10.1038/nm.1917
- ↑ Wang L, Deng W, Shi T, Ma D. URP2SF, a FERM and PH domain containing protein, regulates NF-kappaB and apoptosis. Biochem Biophys Res Commun. 2008 Apr 18;368(4):899-906. doi:, 10.1016/j.bbrc.2008.02.024. Epub 2008 Feb 14. PMID:18280249 doi:https://dx.doi.org/10.1016/j.bbrc.2008.02.024
- ↑ Kuijpers TW, van de Vijver E, Weterman MA, de Boer M, Tool AT, van den Berg TK, Moser M, Jakobs ME, Seeger K, Sanal O, Unal S, Cetin M, Roos D, Verhoeven AJ, Baas F. LAD-1/variant syndrome is caused by mutations in FERMT3. Blood. 2009 May 7;113(19):4740-6. doi: 10.1182/blood-2008-10-182154. Epub 2008, Dec 8. PMID:19064721 doi:https://dx.doi.org/10.1182/blood-2008-10-182154
- ↑ Svensson L, Howarth K, McDowall A, Patzak I, Evans R, Ussar S, Moser M, Metin A, Fried M, Tomlinson I, Hogg N. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med. 2009 Mar;15(3):306-12. doi: 10.1038/nm.1931. Epub 2009 Feb 22. PMID:19234463 doi:https://dx.doi.org/10.1038/nm.1931
- ↑ Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma YQ, Podrez EA, Tosi M, Lennon DP, Caplan AI, Shurin SB, Plow EF, Byzova TV. A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med. 2009 Mar;15(3):313-8. doi: 10.1038/nm.1917. Epub 2009 Feb 22. PMID:19234460 doi:https://dx.doi.org/10.1038/nm.1917
- ↑ Xu Z, Ma S, Zhou Y, Ma YQ. Structural basis of kindlin-3 in leukocyte adhesion deficiency III. J Thromb Haemost. 2026 Jun 26:S1538-7836(26)00406-X. PMID:42362029 doi:10.1016/j.jtha.2026.06.021
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