| Structural highlights
1ljm is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: |
| | Gene: | human (Homo sapiens) |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[RUNX1_HUMAN] Note=A chromosomal aberration involving RUNX1/AML1 is a cause of M2 type acute myeloid leukemia (AML-M2). Translocation t(8;21)(q22;q22) with RUNX1T1.[1] [2] [3] [4] [5] Note=A chromosomal aberration involving RUNX1/AML1 is a cause of therapy-related myelodysplastic syndrome (T-MDS). Translocation t(3;21)(q26;q22) with EAP or MECOM. Note=A chromosomal aberration involving RUNX1/AML1 is a cause of chronic myelogenous leukemia (CML). Translocation t(3;21)(q26;q22) with EAP or MECOM. Note=A chromosomal aberration involving RUNX1/AML1 is found in childhood acute lymphoblastic leukemia (ALL). Translocation t(12;21)(p13;q22) with TEL. The translocation fuses the 3'-end of TEL to the alternate 5'-exon of AML-1H. Note=A chromosomal aberration involving RUNX1 is found in acute leukemia. Translocation t(11,21)(q13;q22) that forms a MACROD1-RUNX1 fusion protein. Defects in RUNX1 are the cause of familial platelet disorder with associated myeloid malignancy (FPDMM) [MIM:601399]. FPDMM is an autosomal dominant disease characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukemia.[6] Note=A chromosomal aberration involving RUNX1/AML1 is found in therapy-related myeloid malignancies. Translocation t(16;21)(q24;q22) that forms a RUNX1-CBFA2T3 fusion protein. Note=A chromosomal aberration involving RUNX1/AML1 is a cause of chronic myelomonocytic leukemia. Inversion inv(21)(q21;q22) with USP16.
Function
[RUNX1_HUMAN] CBF binds to the core site, 5'-PYGPYGGT-3', of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL-3 and GM-CSF promoters. The alpha subunit binds DNA and appears to have a role in the development of normal hematopoiesis. Isoform AML-1L interferes with the transactivation activity of RUNX1. Acts synergistically with ELF4 to transactivate the IL-3 promoter and with ELF2 to transactivate the mouse BLK promoter. Inhibits KAT6B-dependent transcriptional activation.[7] [8] [9] [10]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The Runt domain proteins are transcription regulators of major developmental pathways. Here we present the crystal structures of the Runt domain (RD) of the human protein RUNX1 and its DNA binding site in their free states and compare them with the published crystal structures of RD bound to DNA and to the partner protein CBFbeta. We demonstrate that (1) RD undergoes an allosteric transition upon DNA binding, which is further stabilized by CBFbeta, and that (2) the free DNA target adopts a bent-helical conformation compatible with that of the complex. These findings elucidate the mechanism by which CBFbeta enhances RD binding to DNA as well as the role of the intrinsic conformation of the DNA target in the recognition process.
DNA recognition by the RUNX1 transcription factor is mediated by an allosteric transition in the RUNT domain and by DNA bending.,Bartfeld D, Shimon L, Couture GC, Rabinovich D, Frolow F, Levanon D, Groner Y, Shakked Z Structure. 2002 Oct;10(10):1395-407. PMID:12377125[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nisson PE, Watkins PC, Sacchi N. Transcriptionally active chimeric gene derived from the fusion of the AML1 gene and a novel gene on chromosome 8 in t(8;21) leukemic cells. Cancer Genet Cytogenet. 1992 Oct 15;63(2):81-8. PMID:1423235
- ↑ Kozu T, Miyoshi H, Shimizu K, Maseki N, Kaneko Y, Asou H, Kamada N, Ohki M. Junctions of the AML1/MTG8(ETO) fusion are constant in t(8;21) acute myeloid leukemia detected by reverse transcription polymerase chain reaction. Blood. 1993 Aug 15;82(4):1270-6. PMID:8353289
- ↑ Miyoshi H, Kozu T, Shimizu K, Enomoto K, Maseki N, Kaneko Y, Kamada N, Ohki M. The t(8;21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript. EMBO J. 1993 Jul;12(7):2715-21. PMID:8334990
- ↑ Tighe JE, Calabi F. Alternative, out-of-frame runt/MTG8 transcripts are encoded by the derivative (8) chromosome in the t(8;21) of acute myeloid leukemia M2. Blood. 1994 Oct 1;84(7):2115-21. PMID:7919324
- ↑ Era T, Asou N, Kunisada T, Yamasaki H, Asou H, Kamada N, Nishikawa S, Yamaguchi K, Takatsuki K. Identification of two transcripts of AML1/ETO-fused gene in t(8;21) leukemic cells and expression of wild-type ETO gene in hematopoietic cells. Genes Chromosomes Cancer. 1995 May;13(1):25-33. PMID:7541640
- ↑ Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, Ratajczak J, Resende IC, Haworth C, Hock R, Loh M, Felix C, Roy DC, Busque L, Kurnit D, Willman C, Gewirtz AM, Speck NA, Bushweller JH, Li FP, Gardiner K, Poncz M, Maris JM, Gilliland DG. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999 Oct;23(2):166-75. PMID:10508512 doi:10.1038/13793
- ↑ Mao S, Frank RC, Zhang J, Miyazaki Y, Nimer SD. Functional and physical interactions between AML1 proteins and an ETS protein, MEF: implications for the pathogenesis of t(8;21)-positive leukemias. Mol Cell Biol. 1999 May;19(5):3635-44. PMID:10207087
- ↑ Pelletier N, Champagne N, Stifani S, Yang XJ. MOZ and MORF histone acetyltransferases interact with the Runt-domain transcription factor Runx2. Oncogene. 2002 Apr 18;21(17):2729-40. PMID:11965546 doi:10.1038/sj.onc.1205367
- ↑ Cho JY, Akbarali Y, Zerbini LF, Gu X, Boltax J, Wang Y, Oettgen P, Zhang DE, Libermann TA. Isoforms of the Ets transcription factor NERF/ELF-2 physically interact with AML1 and mediate opposing effects on AML1-mediated transcription of the B cell-specific blk gene. J Biol Chem. 2004 May 7;279(19):19512-22. Epub 2004 Feb 17. PMID:14970218 doi:10.1074/jbc.M309074200
- ↑ Fujimoto T, Anderson K, Jacobsen SE, Nishikawa SI, Nerlov C. Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPalpha interaction. EMBO J. 2007 May 2;26(9):2361-70. Epub 2007 Apr 12. PMID:17431401 doi:10.1038/sj.emboj.7601675
- ↑ Bartfeld D, Shimon L, Couture GC, Rabinovich D, Frolow F, Levanon D, Groner Y, Shakked Z. DNA recognition by the RUNX1 transcription factor is mediated by an allosteric transition in the RUNT domain and by DNA bending. Structure. 2002 Oct;10(10):1395-407. PMID:12377125
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