8e4v | pdb_00008e4v
Solution structure of the WH domain of MORF
Structural highlights
DiseaseKAT6B_HUMAN Genitopatellar syndrome;Noonan syndrome;Blepharophimosis-intellectual disability syndrome, SBBYS type. A chromosomal aberration involving KAT6B may be a cause acute myeloid leukemias. Translocation t(10;16)(q22;p13) with CREBBP.[1] The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionKAT6B_HUMAN Histone acetyltransferase which may be involved in both positive and negative regulation of transcription. Required for RUNX2-dependent transcriptional activation. May be involved in cerebral cortex development. Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity.[2] [3] [4] Publication Abstract from PubMedHuman acetyltransferases MOZ and MORF are implicated in chromosomal translocations associated with aggressive leukemias. Oncogenic translocations involve the far amino terminus of MOZ/MORF, the function of which remains unclear. Here, we identified and characterized two structured winged helix (WH) domains, WH1 and WH2, in MORF and MOZ. WHs bind DNA in a cooperative manner, with WH1 specifically recognizing unmethylated CpG sequences. Structural and genomic analyses show that the DNA binding function of WHs targets MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation, and WH1 recruits oncogenic fusions to HOXA genes that trigger leukemogenesis. Cryo-EM, NMR, mass spectrometry and mutagenesis studies provide mechanistic insight into the DNA-binding mechanism, which includes the association of WH1 with the CpG-containing linker DNA and binding of WH2 to the dyad of the nucleosome. The discovery of WHs in MORF and MOZ and their DNA binding functions could open an avenue in developing therapeutics to treat diseases associated with aberrant MOZ/MORF acetyltransferase activities. MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain.,Becht DC, Klein BJ, Kanai A, Jang SM, Cox KL, Zhou BR, Phanor SK, Zhang Y, Chen RW, Ebmeier CC, Lachance C, Galloy M, Fradet-Turcotte A, Bulyk ML, Bai Y, Poirier MG, Cote J, Yokoyama A, Kutateladze TG Nat Commun. 2023 Feb 8;14(1):697. doi: 10.1038/s41467-023-36368-5. PMID:36754959[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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