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Details on Person UniProt:Q03164 KMT2A
| Class:Id | ReferenceGeneProduct:56674 |
|---|---|
| _chainChangeLog | chain:1-3969 added on Sat February 7 2015;chain:1-2718 added on Sat February 7 2015;chain:2719-3969 added on Sat February 7 2015 |
| _displayName | UniProt:Q03164 KMT2A |
| _timestamp | 2025-02-21 19:39:21 |
| chain | chain:1-3969 chain:1-2718 chain:2719-3969 |
| checksum | 1150F37EAB1430D3 |
| comment | FUNCTION Histone methyltransferase that plays an essential role in early development and hematopoiesis (PubMed:12453419, PubMed:15960975, PubMed:19187761, PubMed:19556245, PubMed:20677832, PubMed:21220120, PubMed:26886794). 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) (PubMed:12453419, PubMed:15960975, PubMed:19187761, PubMed:19556245, PubMed:20677832, PubMed:21220120, PubMed:24235145, PubMed:26886794). 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 (PubMed:12453419, PubMed:15960975, PubMed:19187761, PubMed:19556245, PubMed:20677832, PubMed:21220120, PubMed:25561738, PubMed:26886794). Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity (PubMed:19187761, PubMed:26886794). 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' (PubMed:19187761). Binds to unmethylated CpG elements in the promoter of target genes and helps maintain them in the nonmethylated state (PubMed:20010842). Required for transcriptional activation of HOXA9 (PubMed:12453419, PubMed:20010842, PubMed:20677832). Promotes PPP1R15A-induced apoptosis (PubMed:10490642). 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 (PubMed:24235145).CATALYTIC ACTIVITY L-lysyl(4)-[histone H3] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-homocysteine + H(+)CATALYTIC ACTIVITY N(6)-methyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-homocysteine + H(+)CATALYTIC ACTIVITY L-cysteinyl-[protein] + S-adenosyl-L-methionine = S-methyl-L-cysteinyl-[protein] + S-adenosyl-L-homocysteine + H(+)BIOPHYSICOCHEMICAL PROPERTIES MLL cleavage product N320 heterodimerizes with MLL cleavage product C180 (via SET and FYRC domains). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, HCFC2, WDR5, DPY30 and RBBP5, as well as the facultative components BACC1, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MEN1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15199122, PubMed:15960975, PubMed:17500065, PubMed:19187761, PubMed:19556245, PubMed:23508102, PubMed:26886794). Forms a core complex with the evolutionary conserved subcomplex WRAD composed of WDR5, RBBP5, ASH2L/ASH2 and DPY30 subunits; WRAD differentially stimulates the methyltransferase activity (PubMed:25561738). Interacts (via WIN motif) with WDR5; the interaction is direct (PubMed:18829459, PubMed:18840606, PubMed:19556245, PubMed:22665483). Interaction with WDR5 is required for stable interaction with ASH2L and RBBP5, and thereby also for optimal histone methyltransferase activity (PubMed:26886794). Interacts with KAT8/MOF; the interaction is direct (PubMed:15960975). Interacts with SBF1 and PPP1R15A (PubMed:10490642, PubMed:9537414). Interacts with ZNF335 (PubMed:23178126). Interacts with CLOCK and BMAL1 in a circadian manner (By similarity). Interacts with PPIE; this results in decreased histone H3 methyltransferase activity (PubMed:20541251, PubMed:20677832). Interacts with CREBBP (PubMed:16253272). Interacts with the WRAD complex composed of WDR5, RBBP5, ASH2L and DPY30 (PubMed:22665483). Interacts (via MBM motif) with MEN1 (PubMed:22327296, PubMed:22936661, PubMed:25305204). Interacts (via IBM motifs) with PSIP1 (via IBD domain) with moderate affinity whereas the KMT2A-MEN1 complex interacts with a greater affinity; MEN1 enhances interaction of KMT2A with PSIP1 (PubMed:22327296, PubMed:25082813, PubMed:25305204, PubMed:29997176). Phosphorylation increases its affinity for PSIP1 (PubMed:29997176). Forms a complex with CREBBP and CREB1 (PubMed:23651431).SUBUNIT (Microbial infection) Interacts with herpes virus 8/HHV-8 protein LANA1; this interaction regulates the MLL1 histone methyltransferase activity on viral DNA.INTERACTION Localizes to a diffuse nuclear pattern when not associated with MLL cleavage product N320.ALTERNATIVE PRODUCTS Heart, lung, brain and T- and B-lymphocytes.DOMAIN The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.DOMAIN The SET domain structure is atypical and is not in an optimal position to have methyltransferase activity. It requires other components of the MLL1/MLL complex, such as ASH2L or RBBP5, to order the active site and obtain optimal histone methyltransferase activity.DOMAIN The CXXC-type zinc finger binds to DNA sequence elements containing unnmethylated CpG dinucleotides.DOMAIN The third PHD-type zinc-finger binds both trimethylated histone H3K4me3 and PPIE; histone and PPIE bind to distinct surfaces (PubMed:20541251, PubMed:20677832). Nevertheless, PPIE binding and histone binding are mutually inhibitory (PubMed:20677832). Isomerization of a peptidylproline bond in the linker between the third PHD-type zinc-finger and the bromo domain disrupts the interaction between the bromo domain and the third PHD-type zinc-finger, and thereby facilitates interaction with PPIE (PubMed:20541251).PTM Proteolytic cleavage by TASP1 generates MLL cleavage product N320 and MLL cleavage product C180, which reassemble through a non-covalent association. 2 cleavage sites exist, cleavage site 1 (CS1) and cleavage site 2 (CS2), to generate MLL cleavage products N320 and C180. CS2 is the major site.PTM Phosphorylation increases its interaction with PSIP1.PTM Auto-methylated at Cys-3882: auto-methylation is inhibited by the WRAD complex and unmodified histone H3.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE Chromosomal aberrations involving KMT2A are a cause of acute leukemias. Translocation t(1;11)(q21;q23) with MLLT11/AF1Q; translocation t(3;11)(p21;q23) with NCKIPSD/AF3p21; translocation t(3,11)(q25,q23) with GMPS; translocation t(4;11)(q21;q23) with AFF1/MLLT2/AF4; insertion ins(5;11)(q31;q13q23) with AFF4/AF5Q31; translocation t(5;11)(q12;q23) with AF5-alpha/CENPK; translocation t(6;11)(q27;q23) with AFDN; translocation t(9;11)(p22;q23) with MLLT3/AF9; translocation t(10;11)(p11.2;q23) with ABI1; translocation t(10;11)(p12;q23) with MLLT10/AF10; t(11;15)(q23;q14) with KNL1 and ZFYVE19; translocation t(11;17)(q23;q21) with MLLT6/AF17; translocation t(11;19)(q23;p13.3) with ELL; translocation t(11;19)(q23;p13.3) with MLLT1/ENL; translocation t(11;19)(q23;p23) with GAS7; translocation t(X;11)(q13;q23) with FOXO4/AFX1. Translocation t(3;11)(q28;q23) with LPP. Translocation t(10;11)(q22;q23) with TET1. Translocation t(9;11)(q34;q23) with DAB2IP. Translocation t(4;11)(p12;q23) with FRYL. Fusion proteins KMT2A-MLLT1, KMT2A-MLLT3 and KMT2A-ELL interact with PPP1R15A and, on the contrary to unfused KMT2A, inhibit PPP1R15A-induced apoptosis. Fusion protein KMT2A-MLLT3 interacts with MEN1 and PSIP1 (PubMed:22936661, PubMed:25305204).DISEASE A chromosomal aberration involving KMT2A may be a cause of chronic neutrophilic leukemia. Translocation t(4;11)(q21;q23) with SEPT11.SIMILARITY Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. TRX/MLL subfamily.SEQUENCE CAUTION Contaminating sequence. Potential poly-A sequence. |
| description | recommendedName: Histone-lysine N-methyltransferase 2A shortName: Lysine N-methyltransferase 2A ecNumber evidence="12 23 24 35 38 40"2.1.1.364 alternativeName: fullName evidence="48"ALL-1 alternativeName: CXXC-type zinc finger protein 7 alternativeName: fullName evidence="51"Cysteine methyltransferase KMT2A ecNumber evidence="35"2.1.1.- alternativeName: Myeloid/lymphoid or mixed-lineage leukemia alternativeName: Myeloid/lymphoid or mixed-lineage leukemia protein 1 alternativeName: Trithorax-like protein alternativeName: Zinc finger protein HRX component recommendedName: MLL cleavage product N320 alternativeName: N-terminal cleavage product of 320 kDa shortName: p320 /component component recommendedName: MLL cleavage product C180 alternativeName: C-terminal cleavage product of 180 kDa shortName: p180 /component |
| geneName | KMT2A ALL1 CXXC7 HRX HTRX MLL MLL1 TRX1 |
| identifier | Q03164 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Acetylation Alternative splicing Apoptosis Biological rhythms Bromodomain Chromatin regulator Chromosomal rearrangement Direct protein sequencing DNA-binding Host-virus interaction Isopeptide bond Metal-binding Methylation Methyltransferase Nucleus Phosphoprotein Proteomics identification Proto-oncogene Reference proteome Repeat S-adenosyl-L-methionine Transcription Transcription regulation Transferase Ubl conjugation Zinc Zinc-finger |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 |
| name | KMT2A |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8961120] ENSEMBL:ENSG00000118058 KMT2A [Homo sapiens] |
| secondaryIdentifier | KMT2A_HUMAN E9PQG7 Q13743 Q13744 Q14845 Q16364 Q59FF2 Q6UBD1 Q9HBJ3 Q9UD94 Q9UMA3 |
| sequenceLength | 3969 |
| species | [Species:48887] Homo sapiens |
| (isoformParent) | [ReferenceIsoform:148548] UniProt:Q03164-2 KMT2A [Homo sapiens] [ReferenceIsoform:405114] UniProt:Q03164-1 KMT2A [Homo sapiens] [ReferenceIsoform:8977893] UniProt:Q03164-3 KMT2A [Homo sapiens] |
| (referenceEntity) | [EntityWithAccessionedSequence:1183223] KMT2A [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:8961356] KMT2A [extracellular region] [Homo sapiens] [EntityWithAccessionedSequence:9818584] KMT2A [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:9818590] KMT2A(2719-3969) [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:9818591] KMT2A(1-2718) [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:9818593] KMT2A(2719-3969) [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:9818597] KMT2A(1-2718) [cytosol] [Homo sapiens] |
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No pathways have been reviewed or authored by UniProt:Q03164 KMT2A (56674)
