| Structural highlights
Disease
[ARI5B_HUMAN] Note=Defects in ARID5B may be a cause of susceptibility to coronary atherosclerosis in the Japanese population. Defects in ARID5B may be a cause of susceptibility to acute lymphoblastic leukemia (ALL) [MIM:613065]. Note=ALL is a subtype of acute leukemia, a cancer of the white blood cells. ALL is a malignant disease of bone marrow and the most common malignancy diagnosed in children. The malignant cells are lymphoid precursor cells (lymphoblasts) that are arrested in an early stage of development. The lymphoblasts replace the normal marrow elements, resulting in a marked decrease in the production of normal blood cells. Consequently, anemia, thrombocytopenia, and neutropenia occur to varying degrees. The lymphoblasts also proliferate in organs other than the marrow, particularly the liver, spleen, and lymphonodes.[1] [2] [3] [4] [5] [6] [7]
Function
[ARI5B_HUMAN] Transcription coactivator that binds to the 5'-AATA[CT]-3' core sequence and plays a key role in adipogenesis and liver development. Acts by forming a complex with phosphorylated PHF2, which mediates demethylation at Lys-336, leading to target the PHF2-ARID5B complex to target promoters, where PHF2 mediates demethylation of dimethylated 'Lys-9' of histone H3 (H3K9me2), followed by transcription activation of target genes. The PHF2-ARID5B complex acts as a coactivator of HNF4A in liver. Required for adipogenesis: regulates triglyceride metabolism in adipocytes by regulating expression of adipogenic genes. Overexpression leads to induction of smooth muscle marker genes, suggesting that it may also act as a regulator of smooth muscle cell differentiation and proliferation. Represses the cytomegalovirus enhancer.[8]
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
Understanding the mechanism of protein-DNA interactions at the molecular level is one of the main focuses in structural and molecular biological investigations. At present, NMR spectroscopy is the only approach that can provide atomic details of protein-DNA recognition in solution. However, determining the structures of protein-DNA complexes using NMR spectroscopy has been dependent on the observation of intermolecular nuclear Overhauser effects (NOE) and their assignments, which are difficult to obtain in many cases. In this study, we have shown that intermolecular distance constraints derived from a single spin-label in combination with docking calculations have defined many specific contacts of the complex between the AT-rich interaction domain (ARID) of Mrf2 and its target DNA. Mrf2 contacts DNA mainly using the two flexible loops, L1 and L2. While the L1 loop contacts the phosphate backbone, L2 and several residues in the adjacent helices interact with AT base pairs in the major groove of DNA. Despite the structural diversity in the ARID family of DNA-binding proteins, Mrf2 maintains contacts with DNA similar to those observed in the homologous Dri-DNA complex.
Determination of the three-dimensional structure of the Mrf2-DNA complex using paramagnetic spin labeling.,Cai S, Zhu L, Zhang Z, Chen Y Biochemistry. 2007 May 1;46(17):4943-50. Epub 2007 Apr 4. PMID:17407261[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Trevino LR, Yang W, French D, Hunger SP, Carroll WL, Devidas M, Willman C, Neale G, Downing J, Raimondi SC, Pui CH, Evans WE, Relling MV. Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet. 2009 Sep;41(9):1001-5. doi: 10.1038/ng.432. Epub 2009 Aug 16. PMID:19684603 doi:10.1038/ng.432
- ↑ Papaemmanuil E, Hosking FJ, Vijayakrishnan J, Price A, Olver B, Sheridan E, Kinsey SE, Lightfoot T, Roman E, Irving JA, Allan JM, Tomlinson IP, Taylor M, Greaves M, Houlston RS. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet. 2009 Sep;41(9):1006-10. doi: 10.1038/ng.430. Epub 2009 Aug 16. PMID:19684604 doi:10.1038/ng.430
- ↑ Prasad RB, Hosking FJ, Vijayakrishnan J, Papaemmanuil E, Koehler R, Greaves M, Sheridan E, Gast A, Kinsey SE, Lightfoot T, Roman E, Taylor M, Pritchard-Jones K, Stanulla M, Schrappe M, Bartram CR, Houlston RS, Kumar R, Hemminki K. Verification of the susceptibility loci on 7p12.2, 10q21.2, and 14q11.2 in precursor B-cell acute lymphoblastic leukemia of childhood. Blood. 2010 Mar 4;115(9):1765-7. doi: 10.1182/blood-2009-09-241513. Epub 2009 Dec, 30. PMID:20042726 doi:10.1182/blood-2009-09-241513
- ↑ Healy J, Richer C, Bourgey M, Kritikou EA, Sinnett D. Replication analysis confirms the association of ARID5B with childhood B-cell acute lymphoblastic leukemia. Haematologica. 2010 Sep;95(9):1608-11. doi: 10.3324/haematol.2010.022459. Epub, 2010 May 11. PMID:20460642 doi:10.3324/haematol.2010.022459
- ↑ Yang W, Trevino LR, Yang JJ, Scheet P, Pui CH, Evans WE, Relling MV. ARID5B SNP rs10821936 is associated with risk of childhood acute lymphoblastic leukemia in blacks and contributes to racial differences in leukemia incidence. Leukemia. 2010 Apr;24(4):894-6. doi: 10.1038/leu.2009.277. Epub 2010 Jan 7. PMID:20054350 doi:10.1038/leu.2009.277
- ↑ Han S, Lee KM, Park SK, Lee JE, Ahn HS, Shin HY, Kang HJ, Koo HH, Seo JJ, Choi JE, Ahn YO, Kang D. Genome-wide association study of childhood acute lymphoblastic leukemia in Korea. Leuk Res. 2010 Oct;34(10):1271-4. doi: 10.1016/j.leukres.2010.02.001. Epub 2010, Feb 26. PMID:20189245 doi:10.1016/j.leukres.2010.02.001
- ↑ Paulsson K, Forestier E, Lilljebjorn H, Heldrup J, Behrendtz M, Young BD, Johansson B. Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21719-24. doi:, 10.1073/pnas.1006981107. Epub 2010 Nov 22. PMID:21098271 doi:10.1073/pnas.1006981107
- ↑ Baba A, Ohtake F, Okuno Y, Yokota K, Okada M, Imai Y, Ni M, Meyer CA, Igarashi K, Kanno J, Brown M, Kato S. PKA-dependent regulation of the histone lysine demethylase complex PHF2-ARID5B. Nat Cell Biol. 2011 Jun;13(6):668-75. doi: 10.1038/ncb2228. Epub 2011 May 1. PMID:21532585 doi:10.1038/ncb2228
- ↑ Cai S, Zhu L, Zhang Z, Chen Y. Determination of the three-dimensional structure of the Mrf2-DNA complex using paramagnetic spin labeling. Biochemistry. 2007 May 1;46(17):4943-50. Epub 2007 Apr 4. PMID:17407261 doi:10.1021/bi061738h
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