{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:59:48Z","timestamp":1791809988108,"version":"4.3.4"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2019,9,1]],"date-time":"2019-09-01T00:00:00Z","timestamp":1567296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>CD40L plays a major role in immune response and is a major therapeutic target for inflammation. Integrin \u03b15\u03b21 and CD40 simultaneously bind to CD40L. It is unclear if \u03b15\u03b21 and CD40 work together in CD40\/CD40L signaling or how \u03b15\u03b21 binds to CD40L. In this article, we describe that the integrin-binding site of human CD40L is predicted to be located in the trimeric interface by docking simulation. Mutations in the predicted integrin-binding site markedly reduced the binding of \u03b15\u03b21 to CD40L. Several CD40L mutants defective in integrin binding were defective in NF-\u03baB activation and B cell activation and suppressed CD40L signaling induced by wild-type CD40L; however, they still bound to CD40. These findings suggest that integrin \u03b15\u03b21 binds to monomeric CD40L through the binding site in the trimeric interface of CD40L, and this plays a critical role in CD40\/CD40L signaling. Integrin \u03b1v\u03b23, a widely distributed vascular integrin, bound to CD40L in a KGD-independent manner, suggesting that \u03b1v\u03b23 is a new CD40L receptor. Several missense mutations in CD40L that induce immunodeficiency with hyper-IgM syndrome type 1 (HIGM1) are clustered in the integrin-binding site of the trimeric interface. These HIGM1 CD40L mutants were defective in binding to \u03b15\u03b21 and \u03b1v\u03b23 (but not to CD40), suggesting that the defect in integrin binding may be a causal factor of HIGM1. These findings suggest that \u03b15\u03b21 and \u03b1v\u03b23 bind to the overlapping binding site in the trimeric interface of monomeric CD40L and generate integrin-CD40L-CD40 ternary complex. CD40L mutants defective in integrins have potential as antagonists of CD40\/CD40L signaling.<\/jats:p>","DOI":"10.4049\/jimmunol.1801630","type":"journal-article","created":{"date-parts":[[2019,7,22]],"date-time":"2019-07-22T20:15:11Z","timestamp":1563826511000},"page":"1383-1391","source":"Crossref","is-referenced-by-count":54,"title":["Integrin Binding to the Trimeric Interface of CD40L Plays a Critical Role in CD40\/CD40L Signaling"],"prefix":"10.1093","volume":"203","author":[{"given":"Yoko K","family":"Takada","sequence":"first","affiliation":[{"name":"Department of Dermatology, School of Medicine, University of California , Davis, Sacramento, CA 95817"},{"name":"Department of Biochemistry and Molecular Medicine, School of Medicine, University of California , Davis, Sacramento, CA 95817"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, School of Medicine, University of California , Davis, Sacramento, CA 95817"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiko","family":"Shimoda","sequence":"additional","affiliation":[{"name":"Department of Dermatology, School of Medicine, University of California , Davis, Sacramento, CA 95817"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshikazu","family":"Takada","sequence":"additional","affiliation":[{"name":"Department of Dermatology, School of Medicine, University of California , Davis, Sacramento, CA 95817"},{"name":"Department of Biochemistry and Molecular Medicine, School of Medicine, University of California , Davis, Sacramento, CA 95817"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,9,1]]},"reference":[{"key":"2025030417541414800_r1","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.3389\/fimmu.2017.01791","article-title":"The CD40-CD40L dyad in experimental autoimmune encephalomyelitis and multiple sclerosis","volume":"8","author":"Aarts","year":"2017","journal-title":"Front. 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Rheumatol."},{"key":"2025030417541414800_r7","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.smim.2009.06.004","article-title":"The immunobiology of CD154-CD40-TRAF interactions in atherosclerosis","volume":"21","author":"Engel","year":"2009","journal-title":"Semin. Immunol."},{"key":"2025030417541414800_r8","doi-asserted-by":"crossref","DOI":"10.1155\/2012\/490148","article-title":"CD154: an immunoinflammatory mediator in systemic lupus erythematosus and rheumatoid arthritis","volume":"2012","author":"Alaaeddine","year":"2012","journal-title":"Clin. Dev. 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Chem."},{"key":"2025030417541414800_r15","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1002\/eji.201444941","article-title":"Interaction of CD154 with different receptors and its role in bidirectional signals","volume":"45","author":"Alturaihi","year":"2015","journal-title":"Eur. J. 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Chem."},{"key":"2025030417541414800_r26","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1002\/humu.20405","article-title":"Immunodeficiency mutation databases (IDbases)","volume":"27","author":"Piiril\u00e4","year":"2006","journal-title":"Hum. Mutat."},{"key":"2025030417541414800_r27","doi-asserted-by":"crossref","first-page":"2421","DOI":"10.1182\/blood.V92.7.2421","article-title":"Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome","volume":"92","author":"Seyama","year":"1998","journal-title":"Blood"},{"key":"2025030417541414800_r28","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/(SICI)1098-1004(1996)8:3<223::AID-HUMU5>3.0.CO;2-A","article-title":"Mutation analysis in CD40 ligand deficiency leading to X-linked hypogammaglobulinemia with hyper IgM syndrome","volume":"8","author":"Katz","year":"1996","journal-title":"Hum. 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Invest."},{"key":"2025030417541414800_r32","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1002\/1529-0131(199905)42:5<871::AID-ANR5>3.0.CO;2-J","article-title":"Elevated levels and functional capacity of soluble CD40 ligand in systemic lupus erythematosus sera","volume":"42","author":"Vakkalanka","year":"1999","journal-title":"Arthritis Rheum."},{"key":"2025030417541414800_r33","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1073\/pnas.93.6.2482","article-title":"Ligand occupancy of the alpha-V-beta3 integrin is necessary for smooth muscle cells to migrate in response to insulin-like growth factor","volume":"93","author":"Jones","year":"1996","journal-title":"Proc. Natl. Acad. Sci. 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Chem."},{"key":"2025030417541414800_r36","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0010273","article-title":"A novel fibroblast growth factor-1 (FGF1) mutant that acts as an FGF antagonist","volume":"5","author":"Yamaji","year":"2010","journal-title":"PLoS One"},{"key":"2025030417541414800_r37","article-title":"A dominant-negative FGF1 mutant (the R50E mutant) suppresses tumorigenesis and angiogenesis. [Published erratum appears in 2014 PLoS One 9: e91599.]","volume":"8","author":"Mori","year":"2013","journal-title":"PLoS One"},{"key":"2025030417541414800_r38","doi-asserted-by":"crossref","first-page":"19593","DOI":"10.1074\/jbc.M113.470872","article-title":"An integrin binding-defective mutant of insulin-like growth factor-1 (R36E\/R37E IGF1) acts as a dominant-negative antagonist of the IGF1 receptor (IGF1R) and suppresses tumorigenesis but still binds to IGF1R","volume":"288","author":"Fujita","year":"2013","journal-title":"J. Biol. 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