5ht6
From Proteopedia
Crystal structure of the SET domain of the human MLL5 methyltransferase
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 PubMedMixed Lineage Leukemia 5 (MLL5) plays a key role in hematopoiesis, spermatogenesis and cell cycle progression. Chromatin binding is ensured by its plant homeodomain (PHD) through a direct interaction with the N-terminus of histone H3 (H3). In addition, MLL5 contains a Su(var)3-9, Enhancer of zeste, Trithorax (SET) domain, a protein module that usually displays histone lysine methyltransferase activity. We report here the crystal structure of the unliganded SET domain of human MLL5 at 2.1 A resolution. Although it shows most of the canonical features of other SET domains, both the lack of key residues and the presence in the SET-I subdomain of an unusually large loop preclude the interaction of MLL5 SET with its cofactor and substrate. Accordingly, we show that MLL5 is devoid of any in vitro methyltransferase activity on full-length histones and histone H3 peptides. Hence, the three dimensional structure of MLL5 SET domain unveils the structural basis for its lack of methyltransferase activity and suggests a new regulatory mechanism. The Human Mixed Lineage Leukemia 5 (MLL5), a Sequentially and Structurally Divergent SET Domain-Containing Protein with No Intrinsic Catalytic Activity.,Mas-Y-Mas S, Barbon M, Teyssier C, Demene H, Carvalho JE, Bird LE, Lebedev A, Fattori J, Schubert M, Dumas C, Bourguet W, le Maire A PLoS One. 2016 Nov 3;11(11):e0165139. doi: 10.1371/journal.pone.0165139., eCollection 2016. PMID:27812132[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found See AlsoReferences
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