Histone-lysine N-methyltransferase 2A

UniProt Q03164 Organism Homo sapiens Gene ALL1, CXXC7, HRX, HTRX, KMT2A, MLL, MLL1, TRX1 EC 2.1.1.364, 2.1.1.-

Also known as: ALL1, CXXC7, HRX, HTRX, KMT2A, MLL, MLL1, TRX1

Function

Histone methyltransferase that plays an essential role in early development and hematopoiesis. Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of 'Lys-4' of histone H3 (H3K4me) complex and acetylation of 'Lys-16' of histone H4 (H4K16ac). Catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of 'Lys-4' of histone H3 (H3K4) via a non-processive mechanism. Part of chromatin remodeling machinery predominantly forms H3K4me1 and H3K4me2 methylation marks at active chromatin sites where transcription and DNA repair take place. Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity. Has no activity toward histone H3 phosphorylated on 'Thr-3', less activity toward H3 dimethylated on 'Arg-8' or 'Lys-9', while it has higher activity toward H3 acetylated on 'Lys-9'. Binds to unmethylated CpG elements in the promoter of target genes and helps maintain them in the nonmethylated state. Required for transcriptional activation of HOXA9. Promotes PPP1R15A-induced apoptosis. Plays a critical role in the control of circadian gene expression and is essential for the transcriptional activation mediated by the CLOCK-BMAL1 heterodimer (By similarity). Establishes a permissive chromatin state for circadian transcription by mediating a rhythmic methylation of 'Lys-4' of histone H3 (H3K4me) and this histone modification directs the circadian acetylation at H3K9 and H3K14 allowing the recruitment of CLOCK-BMAL1 to chromatin (By similarity). Also has auto-methylation activity on Cys-3882 in absence of histone H3 substrate.

Classification

Family (Pfam): PF05965 FYRC, PF05964 FYRN, PF00628 PHD, PF00856 SET, PF02008 zf-CXXC, PF13771 zf-HC5HC2H
InterPro: Bromodomain, Bromodomain-like_sf, EPHD, FYrich_C, FYrich_N, KMT2A_2B_SET, KMT2A_ePHD, KMT2A_PHD1, KMT2A_PHD2, KMT2A_PHD3, MeTrfase_trithorax, Post-SET_dom, SET_dom, SET_dom_sf, Znf_CXXC, Znf_FYVE_PHD, Znf_PHD, Znf_PHD-finger, Znf_RING/FYVE/PHD
Functional cluster: Homeobox & Zinc-Finger Transcription Factors

Experimental structures · PDB · 60

2AGH NMR
2J2S NMR
2JYI NMR
2KKF NMR
2KU7 NMR
2KYU NMR
2LXS NMR
2LXT NMR
2MSR NMR
2MTN NMR
2W5Y X-ray 2.00A
2W5Z X-ray 2.20A
… and 48 more

A predicted model is available from AlphaFold.

Gene Ontology · 29

Disease associations

OMIM:159555 RAW:OMIM_159555
Wiedemann-Steiner syndrome MONDO:0011518

Drugs targeting this protein · 1

REVUMENIB SESQUIFUMARATE inhibitor

Related proteins · sequence + function similarity

Histone-lysine N-methyltransferase 2A 0.99
Neuron navigator 1 0.78
Neuron navigator 1 0.78
Transcription factor HIVEP3 0.77
Transcription factor HIVEP3 0.76
Jumonji, AT rich interactive domain protein 2 0.75
Protein AF-17 0.75
Protein SOSEKI 0.75
Histone-lysine N-methyltransferase 2B 0.74
Histone-lysine N-methyltransferase 2B 0.74
Transcription initiation factor TFIID subunit 3 0.74
Splicing factor, arginine/serine-rich 19 0.73

Co-cited proteins · studied together in the literature

GMP synthase [glutamine-hydrolyzing] 1 shared papers
Growth arrest-specific protein 7 1 shared papers
Threonine aspartase 1 1 shared papers
Peptidyl-prolyl cis-trans isomerase E 2 shared papers
Protein furry homolog-like 1 shared papers
WD repeat-containing protein 5 10 shared papers
Protein ENL 2 shared papers
NCK-interacting protein with SH3 domain 1 shared papers
Abl interactor 1 1 shared papers
AF4/FMR2 family member 1 1 shared papers
Centromere protein K 1 shared papers
Histone-lysine N-methyltransferase trithorax 1 shared papers

Literature · 69 cited papers

MLL1 is regulated by KSHV LANA and is important for virus latency. Nucleic Acids Res. · 2021
Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation. Proc. Natl. Acad. Sci. U.S.A. · 2018
DNA Sequence Recognition of Human CXXC Domains and Their Structural Determinants. Structure · 2018
Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat. Struct. Mol. Biol. · 2017
Structural basis for activity regulation of MLL family methyltransferases. Nature · 2016
Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination. Genes Dev. · 2015
Biochemical reconstitution and phylogenetic comparison of human SET1 family core complexes involved in histone methylation. J. Biol. Chem. · 2015
The same site on the integrase-binding domain of lens epithelium-derived growth factor is a therapeutic target for MLL leukemia and HIV. Blood · 2014
Validation and structural characterization of the LEDGF/p75-MLL interface as a new target for the treatment of MLL-dependent leukemia. Cancer Res. · 2014
An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
Automethylation activities within the mixed lineage leukemia-1 (MLL1) core complex reveal evidence supporting a 'two-active site' model for multiple histone H3 lysine 4 methylation. J. Biol. Chem. · 2014
Allosteric communication in the KIX domain proceeds through dynamic repacking of the hydrophobic core. ACS Chem. Biol. · 2013
… and 57 more in the literature graph

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