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| | ==Solution NMR structure of BCoR in complex with AF9 (BCoR-AF9)== | | ==Solution NMR structure of BCoR in complex with AF9 (BCoR-AF9)== |
| - | <StructureSection load='6b7g' size='340' side='right' caption='[[6b7g]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''> | + | <StructureSection load='6b7g' size='340' side='right'caption='[[6b7g]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6b7g]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B7G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B7G FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6b7g]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B7G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6B7G FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2lm0|2lm0]], [[2mv7|2mv7]], [[2n4q|2n4q]]</td></tr> | + | </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=6b7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b7g OCA], [https://pdbe.org/6b7g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6b7g RCSB], [https://www.ebi.ac.uk/pdbsum/6b7g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6b7g ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6b7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b7g OCA], [http://pdbe.org/6b7g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b7g RCSB], [http://www.ebi.ac.uk/pdbsum/6b7g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b7g ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/AF9_HUMAN AF9_HUMAN]] A chromosomal aberration involving MLLT3 is associated with acute leukemias. Translocation t(9;11)(p22;q23) with KMT2A/MLL1. The result is a rogue activator protein. [[http://www.uniprot.org/uniprot/BCOR_HUMAN BCOR_HUMAN]] Defects in BCOR are the cause of microphthalmia syndromic type 2 (MCOPS2) [MIM:[http://omim.org/entry/300166 300166]]. Microphthalmia is a clinically heterogeneous disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. MCOPS2 is a very rare multiple congenital anomaly syndrome characterized by eye anomalies (congenital cataract, microphthalmia, or secondary glaucoma), facial abnormalities (long narrow face, high nasal bridge, pointed nose with cartilages separated at the tip, cleft palate, or submucous cleft palate), cardiac anomalies (atrial septal defect, ventricular septal defect, or floppy mitral valve) and dental abnormalities (canine radiculomegaly, delayed dentition, oligodontia, persistent primary teeth, or variable root length).<ref>PMID:15004558</ref> | + | [https://www.uniprot.org/uniprot/AF9_HUMAN AF9_HUMAN] A chromosomal aberration involving MLLT3 is associated with acute leukemias. Translocation t(9;11)(p22;q23) with KMT2A/MLL1. The result is a rogue activator protein. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/AF9_HUMAN AF9_HUMAN]] Component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA.<ref>PMID:20159561</ref> <ref>PMID:20471948</ref> [[http://www.uniprot.org/uniprot/BCOR_HUMAN BCOR_HUMAN]] Transcriptional corepressor. May specifically inhibit gene expression when recruited to promoter regions by sequence specific DNA-binding proteins such as BCL6 and MLLT3. This repression may be mediated at least in part by histone deacetylase activities which can associate with this corepressor. Involved in the repression of TFAP2A; impairs binding of BCL6 and KDM2B to TFAP2A promoter regions. Via repression of TFAP2A acts as a negative regulator of osteo-dentiogenic capacity in adult stem cells; the function implies inhibition of methylation on histone H3 'Lys-4' (H3K4me3) and 'Lys-36' (H3K36me2).<ref>PMID:10898795</ref> <ref>PMID:15004558</ref> <ref>PMID:19578371</ref> <ref>PMID:18280243</ref> | + | [https://www.uniprot.org/uniprot/AF9_HUMAN AF9_HUMAN] Component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA.<ref>PMID:20159561</ref> <ref>PMID:20471948</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | MLL is a target of chromosomal translocations in acute leukemias with poor prognosis. The common MLL fusion partner AF9 (MLLT3) can directly bind to AF4, DOT1L, BCOR, and CBX8. To delineate the relevance of BCOR and CBX8 binding to MLL-AF9 for leukemogenesis, here we determine protein structures of AF9 complexes with CBX8 and BCOR, and show that binding of all four partners to AF9 is mutually exclusive. Using the structural analyses, we identify point mutations that selectively disrupt AF9 interactions with BCOR and CBX8. In bone marrow stem/progenitor cells expressing point mutant CBX8 or point mutant MLL-AF9, we show that disruption of direct CBX8/MLL-AF9 binding does not impact in vitro cell proliferation, whereas loss of direct BCOR/MLL-AF9 binding causes partial differentiation and increased proliferation. Strikingly, loss of MLL-AF9/BCOR binding abrogated its leukemogenic potential in a mouse model. The MLL-AF9 mutant deficient for BCOR binding reduces the expression of the EYA1 phosphatase and the protein level of c-Myc. Reduction in BCOR binding to MLL-AF9 alters a MYC-driven gene expression program, as well as altering expression of SIX-regulated genes, likely contributing to the observed reduction in the leukemia-initiating cell population. |
| | + | |
| | + | BCOR Binding to MLL-AF9 Is Essential for Leukemia via Altered EYA1, SIX, and MYC Activity.,Schmidt CR, Achille NJ, Kuntimaddi A, Boulton AM, Leach BI, Zhang S, Zeleznik-Le NJ, Bushweller JH Blood Cancer Discov. 2020 Sep;1(2):162-177. doi: 10.1158/2643-3230.BCD-20-0036. PMID:32954361<ref>PMID:32954361</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 6b7g" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bushweller, J H]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Kuntimaddi, A]] | + | [[Category: Large Structures]] |
| - | [[Category: Leach, B I]] | + | [[Category: Bushweller JH]] |
| - | [[Category: Schmidt, C R]] | + | [[Category: Kuntimaddi A]] |
| - | [[Category: Complex]] | + | [[Category: Leach BI]] |
| - | [[Category: Transcription]] | + | [[Category: Schmidt CR]] |
| Structural highlights
Disease
AF9_HUMAN A chromosomal aberration involving MLLT3 is associated with acute leukemias. Translocation t(9;11)(p22;q23) with KMT2A/MLL1. The result is a rogue activator protein.
Function
AF9_HUMAN Component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA.[1] [2]
Publication Abstract from PubMed
MLL is a target of chromosomal translocations in acute leukemias with poor prognosis. The common MLL fusion partner AF9 (MLLT3) can directly bind to AF4, DOT1L, BCOR, and CBX8. To delineate the relevance of BCOR and CBX8 binding to MLL-AF9 for leukemogenesis, here we determine protein structures of AF9 complexes with CBX8 and BCOR, and show that binding of all four partners to AF9 is mutually exclusive. Using the structural analyses, we identify point mutations that selectively disrupt AF9 interactions with BCOR and CBX8. In bone marrow stem/progenitor cells expressing point mutant CBX8 or point mutant MLL-AF9, we show that disruption of direct CBX8/MLL-AF9 binding does not impact in vitro cell proliferation, whereas loss of direct BCOR/MLL-AF9 binding causes partial differentiation and increased proliferation. Strikingly, loss of MLL-AF9/BCOR binding abrogated its leukemogenic potential in a mouse model. The MLL-AF9 mutant deficient for BCOR binding reduces the expression of the EYA1 phosphatase and the protein level of c-Myc. Reduction in BCOR binding to MLL-AF9 alters a MYC-driven gene expression program, as well as altering expression of SIX-regulated genes, likely contributing to the observed reduction in the leukemia-initiating cell population.
BCOR Binding to MLL-AF9 Is Essential for Leukemia via Altered EYA1, SIX, and MYC Activity.,Schmidt CR, Achille NJ, Kuntimaddi A, Boulton AM, Leach BI, Zhang S, Zeleznik-Le NJ, Bushweller JH Blood Cancer Discov. 2020 Sep;1(2):162-177. doi: 10.1158/2643-3230.BCD-20-0036. PMID:32954361[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lin C, Smith ER, Takahashi H, Lai KC, Martin-Brown S, Florens L, Washburn MP, Conaway JW, Conaway RC, Shilatifard A. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell. 2010 Feb 12;37(3):429-37. doi: 10.1016/j.molcel.2010.01.026. PMID:20159561 doi:10.1016/j.molcel.2010.01.026
- ↑ He N, Liu M, Hsu J, Xue Y, Chou S, Burlingame A, Krogan NJ, Alber T, Zhou Q. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell. 2010 May 14;38(3):428-38. doi: 10.1016/j.molcel.2010.04.013. PMID:20471948 doi:10.1016/j.molcel.2010.04.013
- ↑ Schmidt CR, Achille NJ, Kuntimaddi A, Boulton AM, Leach BI, Zhang S, Zeleznik-Le NJ, Bushweller JH. BCOR Binding to MLL-AF9 Is Essential for Leukemia via Altered EYA1, SIX, and MYC Activity. Blood Cancer Discov. 2020 Sep;1(2):162-177. doi: 10.1158/2643-3230.BCD-20-0036. PMID:32954361 doi:http://dx.doi.org/10.1158/2643-3230.BCD-20-0036
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