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Protein

N-lysine methyltransferase KMT5A

Gene

KMT5A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Protein-lysine N-methyltransferase that monomethylates both histones and non-histone proteins. Specifically monomethylates 'Lys-20' of histone H4 (H4K20me1). H4K20me1 is enriched during mitosis and represents a specific tag for epigenetic transcriptional repression. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. Required for cell proliferation, probably by contributing to the maintenance of proper higher-order structure of DNA during mitosis. Involved in chromosome condensation and proper cytokinesis. Nucleosomes are preferred as substrate compared to free histones. Mediates monomethylation of p53/TP53 at 'Lys-382', leading to repress p53/TP53-target genes. Plays a negative role in TGF-beta response regulation and a positive role in cell migration.8 Publications

Caution

It is uncertain whether Met-1 or Met-72 is the initiator.Curated

Catalytic activityi

S-adenosyl-L-methionine + L-lysine-[histone] = S-adenosyl-L-homocysteine + N6-methyl-L-lysine-[histone].PROSITE-ProRule annotation3 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei312S-adenosyl-L-methionine1

GO - Molecular functioni

  • histone-lysine N-methyltransferase activity Source: UniProtKB
  • histone methyltransferase activity (H4-K20 specific) Source: Reactome
  • lysine N-methyltransferase activity Source: Reactome
  • p53 binding Source: UniProtKB
  • protein-lysine N-methyltransferase activity Source: UniProtKB
  • transcription corepressor activity Source: UniProtKB

GO - Biological processi

  • cell cycle Source: UniProtKB-KW
  • cell division Source: UniProtKB-KW
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • negative regulation of transcription by RNA polymerase II Source: UniProtKB
  • peptidyl-lysine monomethylation Source: UniProtKB
  • regulation of DNA damage response, signal transduction by p53 class mediator Source: UniProtKB
  • regulation of signal transduction by p53 class mediator Source: Reactome
  • transcription, DNA-templated Source: UniProtKB-KW

Keywordsi

Molecular functionChromatin regulator, Methyltransferase, Repressor, Transferase
Biological processCell cycle, Cell division, Mitosis, Transcription, Transcription regulation
LigandS-adenosyl-L-methionine

Enzyme and pathway databases

BRENDAi2.1.1.43 2681
ReactomeiR-HSA-2299718 Condensation of Prophase Chromosomes
R-HSA-3214841 PKMTs methylate histone lysines
R-HSA-6804760 Regulation of TP53 Activity through Methylation
SIGNORiQ9NQR1

Names & Taxonomyi

Protein namesi
Recommended name:
N-lysine methyltransferase KMT5ACurated (EC:2.1.1.-)
Alternative name(s):
H4-K20-HMTase KMT5A
Histone-lysine N-methyltransferase KMT5A (EC:2.1.1.43)
Lysine N-methyltransferase 5A
Lysine-specific methylase 5AImported
PR/SET domain-containing protein 07
Short name:
PR-Set7
Short name:
PR/SET07
SET domain-containing protein 8
Gene namesi
Name:KMT5AImported
Synonyms:PRSET7, SET07, SET8, SETD8
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000183955.12
HGNCiHGNC:29489 KMT5A
MIMi607240 gene
neXtProtiNX_Q9NQR1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Chromosome, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi172K → Q: Inhibits the interaction with SIRT2. Increases the number of mitotic foci formation. Does not change methyltransferase activity. 1 Publication1
Mutagenesisi172K → R: Increases the interaction with SIRT2. Reduces the number of mitotic foci formation. Does not change methyltransferase activity. 1 Publication1
Mutagenesisi286Y → A or F: Strongly reduces affinity for histone H4 and abolishes methyltransferase activity. 1 Publication1
Mutagenesisi300E → A: Strongly reduces affinity for histone H4. 1 Publication1
Mutagenesisi311C → A: Strongly reduces affinity for histone H4. 1 Publication1
Mutagenesisi336R → G: Abolishes methyltransferase activity. 2 Publications1
Mutagenesisi340H → A: Strongly decreases methyltransferase activity. 1 Publication1
Mutagenesisi375Y → A: Strongly reduces affinity for histone H4 and methyltransferase activity. 1 Publication1
Mutagenesisi375Y → F: Alters methyltransferase activity, so that both monomethylation and dimethylation take place. 1 Publication1
Mutagenesisi379D → A or N: Abolishes histone H4 binding and methyltransferase activity. 4 Publications1
Mutagenesisi385 – 393Missing : Abolishes methyltransferase activity. 1 Publication9
Mutagenesisi388H → A or E: Strongly reduces affinity for histone H4. 1 Publication1
Mutagenesisi388H → F: Increases affinity for histone H4. 1 Publication1

Organism-specific databases

DisGeNETi387893
OpenTargetsiENSG00000183955
PharmGKBiPA143485616

Chemistry databases

ChEMBLiCHEMBL1795176
GuidetoPHARMACOLOGYi2704

Polymorphism and mutation databases

DMDMi25091219

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001860811 – 393N-lysine methyltransferase KMT5AAdd BLAST393

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei100PhosphoserineCombined sources1
Modified residuei172N6-acetyllysine1 Publication1
Modified residuei181PhosphothreonineCombined sources1

Post-translational modificationi

Acetylated at Lys-172; does not change methyltransferase activity. Deacetylated at Lys-172 by SIRT2; does not change methyltransferase activity.1 Publication
Ubiquitinated and degraded by the DCX(DTL) complex.1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ9NQR1
PaxDbiQ9NQR1
PeptideAtlasiQ9NQR1
PRIDEiQ9NQR1

PTM databases

iPTMnetiQ9NQR1
PhosphoSitePlusiQ9NQR1

Expressioni

Developmental stagei

Not detected during G1 phase. First detected during S through G2 phases, and peaks during mitosis (at protein level).1 Publication

Inductioni

By HCFC1 C-terminal chain, independently of HCFC1 N-terminal chain. Transiently induced by TGF-beta and during the cell cycle.2 Publications

Gene expression databases

BgeeiENSG00000183955
CleanExiHS_SETD8
ExpressionAtlasiQ9NQR1 baseline and differential
GenevisibleiQ9NQR1 HS

Organism-specific databases

HPAiHPA064495

Interactioni

Subunit structurei

Interacts with L3MBTL1. Isoform 2 interacts with SIRT2 (phosphorylated form); the interaction is direct, stimulates KMT5A-mediated methyltransferase activity at histone H4 'Lys-20' (H4K20me1) and is increased in a H2O2-induced oxidative stress-dependent manner.4 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • p53 binding Source: UniProtKB

Protein-protein interaction databases

BioGridi13249022 interactors.
DIPiDIP-39133N
IntActiQ9NQR1 3 interactors.
MINTiQ9NQR1
STRINGi9606.ENSP00000332995

Chemistry databases

BindingDBiQ9NQR1

Structurei

Secondary structure

1393
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi236 – 253Combined sources18
Beta strandi259 – 264Combined sources6
Turni265 – 267Combined sources3
Beta strandi268 – 275Combined sources8
Beta strandi282 – 285Combined sources4
Beta strandi288 – 292Combined sources5
Helixi293 – 303Combined sources11
Helixi307 – 309Combined sources3
Helixi310 – 312Combined sources3
Beta strandi313 – 318Combined sources6
Beta strandi321 – 326Combined sources6
Helixi335 – 337Combined sources3
Beta strandi338 – 340Combined sources3
Beta strandi345 – 353Combined sources9
Beta strandi356 – 365Combined sources10
Beta strandi372 – 375Combined sources4
Helixi382 – 387Combined sources6
Helixi389 – 392Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1ZKKX-ray1.45A/B/C/D231-393[»]
2BQZX-ray1.50A/E233-393[»]
3F9WX-ray1.60A/B/C/D232-393[»]
3F9XX-ray1.25A/B/C/D232-393[»]
3F9YX-ray1.50A/B232-393[»]
3F9ZX-ray1.60A/B/C/D232-393[»]
4IJ8X-ray2.00A/B232-393[»]
5HQ2X-ray4.50M194-393[»]
5T5GX-ray2.10A234-380[»]
5TEGX-ray1.30A/B234-393[»]
5TH7X-ray1.95A/B234-380[»]
5V2NX-ray2.00A231-393[»]
5W1YX-ray1.70A/B232-393[»]
ProteinModelPortaliQ9NQR1
SMRiQ9NQR1
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ9NQR1

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini257 – 378SETPROSITE-ProRule annotationAdd BLAST122

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni267 – 269S-adenosyl-L-methionine binding3
Regioni339 – 340S-adenosyl-L-methionine binding2

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili134 – 163Sequence analysisAdd BLAST30

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi6 – 67Ala-richAdd BLAST62
Compositional biasi29 – 32Poly-Arg4

Domaini

Although the SET domain contains the active site of enzymatic activity, both sequences upstream and downstream of the SET domain are required for methyltransferase activity.

Sequence similaritiesi

Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. PR/SET subfamily.PROSITE-ProRule annotation

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiKOG1085 Eukaryota
COG2940 LUCA
GeneTreeiENSGT00410000025501
HOGENOMiHOG000020818
HOVERGENiHBG067546
InParanoidiQ9NQR1
KOiK11428
OMAiKQFSRGE
OrthoDBiEOG091G0UBI
PhylomeDBiQ9NQR1
TreeFamiTF335181

Family and domain databases

InterProiView protein in InterPro
IPR016858 Hist_H4-K20_MeTrfase
IPR001214 SET_dom
PfamiView protein in Pfam
PF00856 SET, 1 hit
PIRSFiPIRSF027717 Histone_H4-K20_mtfrase, 1 hit
SMARTiView protein in SMART
SM00317 SET, 1 hit
PROSITEiView protein in PROSITE
PS51571 SAM_MT43_PR_SET, 1 hit
PS50280 SET, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9NQR1-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MGEGGAAAAL VAAAAAAAAA AAAVVAGQRR RRLGRRARCH GPGRAAGGKM
60 70 80 90 100
SKPCAVEAAA AAVAATAPGP EMVERRGPGR PRTDGENVFT GQSKIYSYMS
110 120 130 140 150
PNKCSGMRFP LQEENSVTHH EVKCQGKPLA GIYRKREEKR NAGNAVRSAM
160 170 180 190 200
KSEEQKIKDA RKGPLVPFPN QKSEAAEPPK TPPSSCDSTN AAIAKQALKK
210 220 230 240 250
PIKGKQAPRK KAQGKTQQNR KLTDFYPVRR SSRKSKAELQ SEERKRIDEL
260 270 280 290 300
IESGKEEGMK IDLIDGKGRG VIATKQFSRG DFVVEYHGDL IEITDAKKRE
310 320 330 340 350
ALYAQDPSTG CYMYYFQYLS KTYCVDATRE TNRLGRLINH SKCGNCQTKL
360 370 380 390
HDIDGVPHLI LIASRDIAAG EELLYDYGDR SKASIEAHPW LKH
Length:393
Mass (Da):42,890
Last modified:November 15, 2002 - v3
Checksum:i2DCD9B697834B5BD
GO
Isoform 2 (identifier: Q9NQR1-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-41: Missing.
     42-57: PGRAAGGKMSKPCAVE → MARGRKMSKPRAVEAA

Show »
Length:352
Mass (Da):39,223
Checksum:iE0DA1AB9881EE4E6
GO

Sequence cautioni

The sequence AAL40879 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti162 – 163KG → RR in AAF97812 (Ref. 3) Curated2
Sequence conflicti281D → A in AAF97812 (Ref. 3) Curated1
Sequence conflicti343C → R in AAF97812 (Ref. 3) Curated1
Sequence conflicti357P → R in AAH50346 (PubMed:15489334).Curated1
Sequence conflicti373L → P in AAF97812 (Ref. 3) Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0022261 – 41Missing in isoform 2. 3 PublicationsAdd BLAST41
Alternative sequenceiVSP_00222742 – 57PGRAA…PCAVE → MARGRKMSKPRAVEAA in isoform 2. 3 PublicationsAdd BLAST16

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY064546 mRNA Translation: AAL40879.1 Different initiation.
AY102937 mRNA Translation: AAM47033.1
AF287261 mRNA Translation: AAF97812.2
AK292645 mRNA Translation: BAF85334.1
BC050346 mRNA Translation: AAH50346.1
CCDSiCCDS9247.1 [Q9NQR1-2]
RefSeqiNP_001311433.1, NM_001324504.1
NP_001311434.1, NM_001324505.1
NP_001311435.1, NM_001324506.1
NP_065115.3, NM_020382.4 [Q9NQR1-2]
UniGeneiHs.443735
Hs.572262

Genome annotation databases

EnsembliENST00000402868; ENSP00000384629; ENSG00000183955 [Q9NQR1-2]
GeneIDi387893
KEGGihsa:387893
UCSCiuc001uew.4 human [Q9NQR1-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiKMT5A_HUMAN
AccessioniPrimary (citable) accession number: Q9NQR1
Secondary accession number(s): A8K9D0, Q86W83, Q8TD09
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 15, 2002
Last sequence update: November 15, 2002
Last modified: April 25, 2018
This is version 167 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome