{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:15:28Z","timestamp":1790615728141,"version":"4.1.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T00:00:00Z","timestamp":1612310400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["GNT1079648"],"award-info":[{"award-number":["GNT1079648"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000995","name":"Australian National University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000995","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,2,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Interferon regulatory factor 4 (IRF4) is a key transcription factor (TF) in the regulation of immune cells, including B and T cells. It acts by binding DNA as both a homodimer and, in conjunction with other TFs, as a heterodimer. The choice of homo and heterodimeric\/ DNA interactions is a critical aspect in the control of the transcriptional program and cell fate outcome. To characterize the nature of this interaction in the homodimeric complex, we have determined the crystal structure of the IRF4\/ISRE homodimeric complex. We show that the complex formation is aided by a substantial DNA deformation with co-operative binding achieved exclusively through protein\u2013DNA contact. This markedly contrasts with the heterodimeric form where DNA bound IRF4 is shown to physically interact with PU.1 TF to engage EICE1. We also show that the hotspot residues (Arg98, Cys99 and Asn102) contact both consensus and non-consensus sequences with the L1 loop exhibiting marked flexibility. Additionally, we identified that IRF4L116R, a mutant associated with chronic lymphocytic leukemia, binds more robustly to DNA thereby providing a rationale for the observed gain of function. Together, we demonstrate key structural differences between IRF4 homo and heterodimeric complexes, thereby providing molecular insights into IRF4-mediated transcriptional regulation.<\/jats:p>","DOI":"10.1093\/nar\/gkaa1287","type":"journal-article","created":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T11:53:14Z","timestamp":1612353194000},"page":"2255-2265","source":"Crossref","is-referenced-by-count":31,"title":["Structural determinants of the IRF4\/DNA homodimeric complex"],"prefix":"10.1093","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9112-2454","authenticated-orcid":false,"given":"Srinivasan","family":"Sundararaj","sequence":"first","affiliation":[{"name":"Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra 2600, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5626-7968","authenticated-orcid":false,"given":"Sandali","family":"Seneviratne","sequence":"additional","affiliation":[{"name":"Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra 2600, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4781-6261","authenticated-orcid":false,"given":"Simon J","family":"Williams","sequence":"additional","affiliation":[{"name":"Research School of Biology, Australian National University, Canberra\u00a02600, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5933-6463","authenticated-orcid":false,"given":"Anselm","family":"Enders","sequence":"additional","affiliation":[{"name":"Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra 2600, Australia"},{"name":"Center for Personalised Immunology, John Curtin School of Medical Research, Australian National University, Canberra 2600, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0571-7671","authenticated-orcid":false,"given":"Marco G","family":"Casarotto","sequence":"additional","affiliation":[{"name":"Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra 2600, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,2,3]]},"reference":[{"key":"2021022716370529200_B1","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1146\/annurev.immunol.19.1.623","article-title":"IRF family of transcription factors as regulators of host defense","volume":"19","author":"Taniguchi","year":"2001","journal-title":"Annu. Rev. Immunol."},{"key":"2021022716370529200_B2","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1089\/jir.2009.0030","article-title":"Interferon regulatory factors in hematopoietic cell differentiation and immune regulation","volume":"29","author":"Battistini","year":"2009","journal-title":"J. Interferon Cytokine Res."},{"key":"2021022716370529200_B3","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1196\/annals.1299.042","article-title":"Convergence of the NF-kappaB and interferon signaling pathways in the regulation of antiviral defense and apoptosis","volume":"1010","author":"Hiscott","year":"2003","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2021022716370529200_B4","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.biochi.2007.01.014","article-title":"The IRF family, revisited","volume":"89","author":"Paun","year":"2007","journal-title":"Biochimie"},{"key":"2021022716370529200_B5","doi-asserted-by":"crossref","first-page":"20065","DOI":"10.1074\/jbc.R700003200","article-title":"The interferon regulatory factor family in host defense: mechanism of action","volume":"282","author":"Ozato","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2021022716370529200_B6","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/0092-8674(87)90288-1","article-title":"Interferon-beta gene regulation: tandemly repeated sequences of a synthetic 6 bp oligomer function as a virus-inducible enhancer","volume":"49","author":"Fujita","year":"1987","journal-title":"Cell"},{"key":"2021022716370529200_B7","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1007\/s12272-016-0854-1","article-title":"Essential role of interferon regulatory factor 4 (IRF4) in immune cell development","volume":"39","author":"Nam","year":"2016","journal-title":"Arch. Pharm. Res."},{"key":"2021022716370529200_B8","doi-asserted-by":"crossref","first-page":"3715","DOI":"10.4049\/jimmunol.1701385","article-title":"Critical functions of IRF4 in B and T lymphocytes","volume":"199","author":"Hagman","year":"2017","journal-title":"J. Immunol."},{"key":"2021022716370529200_B9","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1002\/eji.201344279","article-title":"IRF4 at the crossroads of effector T-cell fate decision","volume":"44","author":"Huber","year":"2014","journal-title":"Eur. J. Immunol."},{"key":"2021022716370529200_B10","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s11515-014-1318-y","article-title":"IRF4 and IRF8: governing the virtues of B lymphocytes","volume":"9","author":"Shukla","year":"2014","journal-title":"Front. Biol."},{"key":"2021022716370529200_B11","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.it.2008.07.006","article-title":"Interferon regulatory factor 4 and 8 in B-cell development","volume":"29","author":"Lu","year":"2008","journal-title":"Trends Immunol."},{"key":"2021022716370529200_B12","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1038\/ng.219","article-title":"A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia","volume":"40","author":"Di\u00a0Bernardo","year":"2008","journal-title":"Nat. Genet."},{"key":"2021022716370529200_B13","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1182\/blood-2011-04-350579","article-title":"IRF4 mutations in chronic lymphocytic leukemia","volume":"118","author":"Havelange","year":"2011","journal-title":"Blood"},{"key":"2021022716370529200_B14","doi-asserted-by":"crossref","first-page":"D941","DOI":"10.1093\/nar\/gky1015","article-title":"COSMIC: the catalogue of somatic mutations in cancer","volume":"47","author":"Tate","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2021022716370529200_B15","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nature09837","article-title":"Initial genome sequencing and analysis of multiple myeloma","volume":"471","author":"Chapman","year":"2011","journal-title":"Nature"},{"key":"2021022716370529200_B16","doi-asserted-by":"crossref","first-page":"3911","DOI":"10.1200\/JCO.2014.59.1503","article-title":"Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma","volume":"33","author":"Walker","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"2021022716370529200_B17","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1038\/leu.2014.13","article-title":"Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma","volume":"28","author":"Melchor","year":"2014","journal-title":"Leukemia"},{"key":"2021022716370529200_B18","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/nature07064","article-title":"IRF4 addiction in multiple myeloma","volume":"454","author":"Shaffer","year":"2008","journal-title":"Nature"},{"key":"2021022716370529200_B19","doi-asserted-by":"crossref","first-page":"27779","DOI":"10.1074\/jbc.M115.678789","article-title":"Structural studies of IRF4 reveal a flexible autoinhibitory region and a compact linker domain","volume":"290","author":"Remesh","year":"2015","journal-title":"J. Biol. Chem."},{"key":"2021022716370529200_B20","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/34224","article-title":"Structure of IRF-1 with bound DNA reveals determinants of interferon regulation","volume":"391","author":"Escalante","year":"1998","journal-title":"Nature"},{"key":"2021022716370529200_B21","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1101\/gad.10.18.2335","article-title":"Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1","volume":"10","author":"Brass","year":"1996","journal-title":"Genes Dev."},{"key":"2021022716370529200_B22","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1002\/eji.201847530","article-title":"A hyperactive mutant of interferon-regulatory factor 4","volume":"49","author":"Kang","year":"2019","journal-title":"Eur. J. Immunol."},{"key":"2021022716370529200_B23","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/nature11530","article-title":"BATF-JUN is critical for IRF4-mediated transcription in T cells","volume":"490","author":"Li","year":"2012","journal-title":"Nature"},{"key":"2021022716370529200_B24","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.immuni.2013.04.009","article-title":"Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4","volume":"38","author":"Ochiai","year":"2013","journal-title":"Immunity"},{"key":"2021022716370529200_B25","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.immuni.2006.07.009","article-title":"Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation","volume":"25","author":"Sciammas","year":"2006","journal-title":"Immunity"},{"key":"2021022716370529200_B26","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/ni1357","article-title":"Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination","volume":"7","author":"Klein","year":"2006","journal-title":"Nat. Immunol."},{"key":"2021022716370529200_B27","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1093\/emboj\/18.4.977","article-title":"Assembly requirements of PU.1-Pip (IRF-4) activator complexes: inhibiting function in vivo using fused dimers","volume":"18","author":"Brass","year":"1999","journal-title":"EMBO J."},{"key":"2021022716370529200_B28","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1016\/S1097-2765(02)00703-7","article-title":"Crystal structure of PU.1\/IRF-4\/DNA ternary complex","volume":"10","author":"Escalante","year":"2002","journal-title":"Mol. Cell"},{"key":"2021022716370529200_B29","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1126\/science.1228309","article-title":"A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes","volume":"338","author":"Glasmacher","year":"2012","journal-title":"Science"},{"key":"2021022716370529200_B30","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/nature11531","article-title":"Compensatory dendritic cell development mediated by BATF-IRF interactions","volume":"490","author":"Tussiwand","year":"2012","journal-title":"Nature"},{"key":"2021022716370529200_B31","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1107\/S0907444909047337","article-title":"XDS","volume":"66","author":"Kabsch","year":"2010","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"2021022716370529200_B32","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1107\/S0907444913000061","article-title":"How good are my data and what is the resolution","volume":"69","author":"Evans","year":"2013","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"2021022716370529200_B33","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1107\/S0907444910045749","article-title":"Overview of the CCP4 suite and current developments","volume":"67","author":"Winn","year":"2011","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"2021022716370529200_B34","doi-asserted-by":"crossref","first-page":"5028","DOI":"10.1093\/emboj\/18.18.5028","article-title":"Crystal structure of an IRF-DNA complex reveals novel DNA recognition and cooperative binding to a tandem repeat of core sequences","volume":"18","author":"Fujii","year":"1999","journal-title":"EMBO J."},{"key":"2021022716370529200_B35","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and development of Coot","volume":"66","author":"Emsley","year":"2010","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"2021022716370529200_B36","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX: a comprehensive Python-based system for macromolecular structure solution","volume":"66","author":"Adams","year":"2010","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"2021022716370529200_B37","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1126\/science.1653449","article-title":"Crystal structure of a CAP-DNA complex: the DNA is bent by 90 degrees","volume":"253","author":"Schultz","year":"1991","journal-title":"Science"},{"key":"2021022716370529200_B38","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/364412a0","article-title":"Co-crystal structure of the HNF-3\/fork head DNA-recognition motif resembles histone H5","volume":"364","author":"Clark","year":"1993","journal-title":"Nature"},{"key":"2021022716370529200_B39","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/0092-8674(90)90453-L","article-title":"Crystal structure of an engrailed homeodomain-DNA complex at 2.8 A resolution: a framework for understanding homeodomain-DNA interactions","volume":"63","author":"Kissinger","year":"1990","journal-title":"Cell"},{"key":"2021022716370529200_B40","doi-asserted-by":"crossref","first-page":"5917","DOI":"10.1093\/nar\/gkp608","article-title":"Conformational analysis of nucleic acids revisited: Curves+","volume":"37","author":"Lavery","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2021022716370529200_B41","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1101\/gad.10.1.27","article-title":"Oct-1 POU domain-DNA interactions: cooperative binding of isolated subdomains and effects of covalent linkage","volume":"10","author":"Klemm","year":"1996","journal-title":"Genes Dev."},{"key":"2021022716370529200_B42","doi-asserted-by":"crossref","first-page":"4384","DOI":"10.1038\/sj.emboj.7600453","article-title":"Crystal structure of ATF-2\/c-Jun and IRF-3 bound to the interferon-beta enhancer","volume":"23","author":"Panne","year":"2004","journal-title":"EMBO J."},{"key":"2021022716370529200_B43","doi-asserted-by":"crossref","first-page":"5046","DOI":"10.1073\/pnas.91.11.5046","article-title":"Molecular interactions between interferon consensus sequence binding protein and members of the interferon regulatory factor family","volume":"91","author":"Bovolenta","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021022716370529200_B44","doi-asserted-by":"crossref","first-page":"7300","DOI":"10.1093\/nar\/gkr325","article-title":"Structures of apo IRF-3 and IRF-7 DNA binding domains: effect of loop L1 on DNA binding","volume":"39","author":"De\u00a0Ioannes","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"2021022716370529200_B45","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.molcel.2007.04.022","article-title":"Structure of IRF-3 bound to the PRDIII-I regulatory element of the human interferon-beta enhancer","volume":"26","author":"Escalante","year":"2007","journal-title":"Mol. Cell"},{"key":"2021022716370529200_B46","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.cell.2007.05.019","article-title":"An atomic model of the interferon-beta enhanceosome","volume":"129","author":"Panne","year":"2007","journal-title":"Cell"}],"container-title":["Nucleic Acids Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/nar\/article-pdf\/49\/4\/2255\/36398605\/gkaa1287.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/nar\/article-pdf\/49\/4\/2255\/36398605\/gkaa1287.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,27]],"date-time":"2021-02-27T11:44:41Z","timestamp":1614426281000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nar\/article\/49\/4\/2255\/6127265"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,3]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2,3]]},"published-print":{"date-parts":[[2021,2,26]]}},"URL":"https:\/\/doi.org\/10.1093\/nar\/gkaa1287","relation":{},"ISSN":["0305-1048","1362-4962"],"issn-type":[{"value":"0305-1048","type":"print"},{"value":"1362-4962","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,2,26]]},"published":{"date-parts":[[2021,2,3]]}}}