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Protein

N-lysine methyltransferase KMT5A

Gene

KMT5A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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

Catalytic activityi

S-adenosyl-L-methionine + L-lysine-[histone] = S-adenosyl-L-homocysteine + N(6)-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 division Source: UniProtKB-KW
  • mitotic nuclear division Source: UniProtKB-KW
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter 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
Complete GO annotation...

Keywords - Molecular functioni

Chromatin regulator, Methyltransferase, Repressor, Transferase

Keywords - Biological processi

Cell cycle, Cell division, Mitosis, Transcription, Transcription regulation

Keywords - Ligandi

S-adenosyl-L-methionine

Enzyme and pathway databases

BioCyciZFISH:HS11381-MONOMER.
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

HGNCiHGNC:29489. KMT5A.

Subcellular locationi

  • Nucleus
  • Chromosome

  • Note: Specifically localizes to mitotic chromosomes. Colocalized with SIRT2 at mitotic foci. Associates with chromosomes during mitosis; association is increased in a H2O(2)-induced oxidative stress-dependent manner. Associates with silent chromatin on euchromatic arms. Not associated with constitutive heterochromatin.

GO - Cellular componenti

Complete GO annotation...

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 H2O(2)-induced oxidative stress-dependent manner.4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
HIST2H4BP628055EBI-1268946,EBI-302023
TWIST1Q156725EBI-1268946,EBI-1797287

GO - Molecular functioni

  • p53 binding Source: UniProtKB

Protein-protein interaction databases

BioGridi132490. 22 interactors.
DIPiDIP-39133N.
IntActiQ9NQR1. 3 interactors.
MINTiMINT-3072203.
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
Helixi306 – 309Combined sources4
Helixi310 – 312Combined sources3
Beta strandi313 – 318Combined sources6
Beta strandi321 – 326Combined sources6
Helixi335 – 337Combined sources3
Beta strandi345 – 353Combined sources9
Beta strandi356 – 365Combined sources10
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[»]
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
Contains 1 SET domain.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

InterProiIPR016858. Hist_H4-K20_MeTrfase.
IPR001214. SET_dom.
[Graphical view]
PfamiPF00856. SET. 1 hit.
[Graphical view]
SMARTiSM00317. SET. 1 hit.
[Graphical view]
PROSITEiPS51571. SAM_MT43_PR_SET. 1 hit.
PS50280. SET. 1 hit.
[Graphical view]

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

Cross-referencesi

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.

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[»]
ProteinModelPortaliQ9NQR1.
SMRiQ9NQR1.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi132490. 22 interactors.
DIPiDIP-39133N.
IntActiQ9NQR1. 3 interactors.
MINTiMINT-3072203.
STRINGi9606.ENSP00000332995.

Chemistry databases

BindingDBiQ9NQR1.
ChEMBLiCHEMBL1795176.
GuidetoPHARMACOLOGYi2704.

PTM databases

iPTMnetiQ9NQR1.
PhosphoSitePlusiQ9NQR1.

Polymorphism and mutation databases

DMDMi25091219.

Proteomic databases

MaxQBiQ9NQR1.
PaxDbiQ9NQR1.
PeptideAtlasiQ9NQR1.
PRIDEiQ9NQR1.

Protocols and materials databases

DNASUi387893.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi387893.
DisGeNETi387893.
GeneCardsiSETD8.
H-InvDBHIX0037637.
HGNCiHGNC:29489. KMT5A.
HPAiHPA064495.
MIMi607240. gene.
neXtProtiNX_Q9NQR1.
OpenTargetsiENSG00000183955.
PharmGKBiPA143485616.
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

BioCyciZFISH:HS11381-MONOMER.
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.

Miscellaneous databases

EvolutionaryTraceiQ9NQR1.
GeneWikiiSETD8.
GenomeRNAii387893.
PROiQ9NQR1.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000183955.
CleanExiHS_SETD8.
ExpressionAtlasiQ9NQR1. baseline and differential.
GenevisibleiQ9NQR1. HS.

Family and domain databases

InterProiIPR016858. Hist_H4-K20_MeTrfase.
IPR001214. SET_dom.
[Graphical view]
PfamiPF00856. SET. 1 hit.
[Graphical view]
SMARTiSM00317. SET. 1 hit.
[Graphical view]
PROSITEiPS51571. SAM_MT43_PR_SET. 1 hit.
PS50280. SET. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiKMT5A_HUMAN
AccessioniPrimary (citable) accession number: Q9NQR1
Secondary accession number(s): A8K9D0, Q86W83, Q8TD09
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 15, 2002
Last sequence update: November 15, 2002
Last modified: November 30, 2016
This is version 158 of the entry and version 3 of the sequence. [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

Caution

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

Keywords - Technical termi

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

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.