7rh2
From Proteopedia
(Difference between revisions)
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| - | ==== | + | ==IRF4 Transcription factor mutant -K59R== |
| - | <StructureSection load='7rh2' size='340' side='right'caption='[[7rh2]]' scene=''> | + | <StructureSection load='7rh2' size='340' side='right'caption='[[7rh2]], [[Resolution|resolution]] 2.47Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7rh2]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RH2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RH2 FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7rh2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rh2 OCA], [https://pdbe.org/7rh2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rh2 RCSB], [https://www.ebi.ac.uk/pdbsum/7rh2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rh2 ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.47Å</td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7rh2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rh2 OCA], [https://pdbe.org/7rh2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rh2 RCSB], [https://www.ebi.ac.uk/pdbsum/7rh2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rh2 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/IRF4_HUMAN IRF4_HUMAN] Defects in IRF4 are a cause of multiple myeloma (MM) [MIM:[https://omim.org/entry/254500 254500]. MM is a malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. Note=A chromosomal aberration involving IRF4 is found in multiple myeloma. Translocation t(6;14)(p25;q32) with the IgH locus. | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/IRF4_HUMAN IRF4_HUMAN] Transcriptional activator. Binds to the interferon-stimulated response element (ISRE) of the MHC class I promoter. Binds the immunoglobulin lambda light chain enhancer, together with PU.1. Probably plays a role in ISRE-targeted signal transduction mechanisms specific to lymphoid cells. Involved in CD8(+) dendritic cell differentiation by forming a complex with the BATF-JUNB heterodimer in immune cells, leading to recognition of AICE sequence (5'-TGAnTCA/GAAA-3'), an immune-specific regulatory element, followed by cooperative binding of BATF and IRF4 and activation of genes (By similarity). | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Interferon regulatory factor 4 (IRF4) is an essential regulator in the development of many immune cells, including B- and T-cells and has been implicated directly in numerous hematological malignancies, including adult T-cell leukemia/lymphoma (ATLL). Recently, an activating mutation in the DNA-binding domain of IRF4 (IRF4(K59R) ) was found as a recurrent somatic mutation in ATLL patients. However, it remains unknown how this mutation gives rise to the observed oncogenic effect. To understand the mode of IRF4(K59R) -mediated gain of function in ATLL pathogenesis, we have determined the structural and affinity basis of IRF4(K59R) /DNA homodimer complex using X-ray crystallography and surface plasmon resonance. Our study shows that arginine substitution (R59) results in the reorientation of the side chain, enabling the guanidium group to interact with the phosphate backbone of the DNA helix. This markedly contrasts with the IRF4(WT) wherein the K59 interacts exclusively with DNA bases. Further, the arginine mutation causes enhanced DNA bending, enabling the IRF4(K59R) to interact more robustly with known DNA targets, as evidenced by increased binding affinity of the protein-DNA complex. Together, we demonstrate how key structural features underpin the basis for this activating mutation, thereby providing a molecular rationale for IRF4(K59R) -mediated ATLL development. | ||
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| + | The molecular basis for the development of adult T-cell leukemia/lymphoma in patients with an IRF4(K59R) mutation.,Sundararaj S, Seneviratne S, Williams SJ, Enders A, Casarotto MG Protein Sci. 2022 Apr;31(4):787-796. doi: 10.1002/pro.4260. Epub 2022 Feb 15. PMID:34913532<ref>PMID:34913532</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7rh2" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: | + | [[Category: Casarotto MG]] |
| + | [[Category: Sundararaj S]] | ||
| + | [[Category: Williams SJ]] | ||
Current revision
IRF4 Transcription factor mutant -K59R
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