4l58
Crystal structure of the MLL5 PHD finger in complex with H3K4me3
Structural highlights
FunctionKMT2E_HUMAN Histone methyltransferase that specifically mono- and dimethylates 'Lys-4' of histone H3 (H3K4me1 and H3K4me2). H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. Key regulator of hematopoiesis involved in terminal myeloid differentiation and in the regulation of hematopoietic stem cell (HSCs) self-renewal by a mechanism that involves DNA methylation. Plays an essential role in retinoic-acid-induced granulopoiesis by acting as a coactivator of RAR-alpha (RARA) in target gene promoters. Also acts as an important cell cycle regulator, participating in cell cycle regulatory network machinery at multiple cell cycle stages. Required to suppress inappropriate expression of S-phase-promoting genes and maintain expression of determination genes in quiescent cells. Overexpression inhibits cell cycle progression, while knockdown induces cell cycle arrest at both the G1 and G2/M phases. Isoform NKp44L: Cellular ligand for NCR2/NKp44, may play a role as a danger signal in cytotoxicity and NK-cell-mediated innate immunity. Publication Abstract from PubMedThe human mixed-lineage leukemia 5 (MLL5) protein mediates hematopoietic cell homeostasis, cell cycle, and survival; however, the molecular basis underlying MLL5 activities remains unknown. Here, we show that MLL5 is recruited to gene-rich euchromatic regions via the interaction of its plant homeodomain finger with the histone mark H3K4me3. The 1.48-A resolution crystal structure of MLL5 plant homeodomain in complex with the H3K4me3 peptide reveals a noncanonical binding mechanism, whereby K4me3 is recognized through a single aromatic residue and an aspartate. The binding induces a unique His-Asp swapping rearrangement mediated by a C-terminal alpha-helix. Phosphorylation of H3T3 and H3T6 abrogates the association with H3K4me3 in vitro and in vivo, releasing MLL5 from chromatin in mitosis. This regulatory switch is conserved in the Drosophila ortholog of MLL5, UpSET, and suggests the developmental control for targeting of H3K4me3. Together, our findings provide first insights into the molecular basis for the recruitment, exclusion, and regulation of MLL5 at chromatin. Molecular basis for chromatin binding and regulation of MLL5.,Ali M, Rincon-Arano H, Zhao W, Rothbart SB, Tong Q, Parkhurst SM, Strahl BD, Deng LW, Groudine M, Kutateladze TG Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11296-301. doi:, 10.1073/pnas.1310156110. Epub 2013 Jun 24. PMID:23798402[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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