METTL21A

gene
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Also known as LOC151194HCA557bHSPA-KMT

Summary

METTL21A (methyltransferase 21A, HSPA lysine, HGNC:30476) is a protein-coding gene on chromosome 2q33.3, encoding Protein N-lysine methyltransferase METTL21A (Q8WXB1). Protein-lysine methyltransferase that selectively trimethylates residues in heat shock protein 70 (HSP70) family members.

Enables ATPase binding activity; Hsp70 protein binding activity; and protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine methylation. Part of protein-containing complex.

Source: NCBI Gene 151194 — RefSeq curated summary.

At a glance

  • GWAS associations: 7
  • Clinical variants (ClinVar): 30 total
  • Druggable target: yes
  • MANE Select transcript: NM_001127395

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:30476
Approved symbolMETTL21A
Namemethyltransferase 21A, HSPA lysine
Location2q33.3
Locus typegene with protein product
StatusApproved
AliasesLOC151194, HCA557b, HSPA-KMT
Ensembl geneENSG00000144401
Ensembl biotypeprotein_coding
OMIM615257
Entrez151194

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 19 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000272839, ENST00000406927, ENST00000411432, ENST00000425132, ENST00000426075, ENST00000432416, ENST00000442521, ENST00000448007, ENST00000448823, ENST00000458426, ENST00000461419, ENST00000471128, ENST00000477919, ENST00000861060, ENST00000861061, ENST00000861062, ENST00000861063, ENST00000861064, ENST00000921189, ENST00000921190, ENST00000921191, ENST00000951163

RefSeq mRNA: 25 — MANE Select: NM_001127395 NM_001127395, NM_001308021, NM_001330130, NM_001330131, NM_001330132, NM_001330133, NM_001330134, NM_001330135, NM_001330136, NM_001330137, NM_001388427, NM_001388439, NM_001393563, NM_001393564, NM_001393565, NM_001393566, NM_001393567, NM_001393569, NM_001393570, NM_001393571, NM_001393572, NM_001393573, NM_001393574, NM_001393575, NM_145280

CCDS: CCDS2376, CCDS77514, CCDS82562, CCDS82563

Canonical transcript exons

ENST00000411432 — 4 exons

ExonStartEnd
ENSE00001623898207625062207625394
ENSE00001804558207612739207613443
ENSE00003460231207624229207624404
ENSE00003571470207621806207621917

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 98.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.8683 / max 58.3984, expressed in 1756 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter IDTPM avgSamples expressed
334083.96251648
334093.19731179
334070.8808404
334100.8277450

Top tissues by expression

253 total, by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
oocyteCL:000002398.10gold quality
secondary oocyteCL:000065597.47gold quality
monocyteCL:000057689.86gold quality
leukocyteCL:000073889.76gold quality
C1 segment of cervical spinal cordUBERON:000646988.02gold quality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099187.95gold quality
mucosa of transverse colonUBERON:000499187.28gold quality
prefrontal cortexUBERON:000045187.22gold quality
spinal cordUBERON:000224086.97gold quality
right lobe of liverUBERON:000111486.78gold quality
anterior cingulate cortexUBERON:000983586.24gold quality
Brodmann (1909) area 9UBERON:001354086.19gold quality
granulocyteCL:000009486.09gold quality
adrenal tissueUBERON:001830385.97gold quality
putamenUBERON:000187485.87gold quality
bone marrowUBERON:000237185.87gold quality
caudate nucleusUBERON:000187385.84gold quality
biceps brachiiUBERON:000150785.81gold quality
dorsolateral prefrontal cortexUBERON:000983485.81gold quality
hypothalamusUBERON:000189885.56gold quality
ventricular zoneUBERON:000305385.26gold quality
calcaneal tendonUBERON:000370185.26gold quality
lymph nodeUBERON:000002984.75gold quality
skeletal muscle tissue of biceps brachiiUBERON:000450284.74silver quality
right frontal lobeUBERON:000281084.73gold quality
bone marrow cellCL:000209284.72gold quality
amygdalaUBERON:000187684.67gold quality
nucleus accumbensUBERON:000188284.63gold quality
neocortexUBERON:000195084.51gold quality
frontal cortexUBERON:000187084.49gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

ExperimentMarker?Max mean expression
E-ANND-3no0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

149 targeting METTL21A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-5011-5P100.0083.465820
HSA-MIR-6867-5P100.0082.213464
HSA-MIR-190A-3P100.0080.355520
HSA-MIR-6851-5P100.0065.631294
HSA-MIR-3689D100.0066.141181
HSA-MIR-4510100.0066.602050
HSA-MIR-6127100.0066.762188
HSA-MIR-6129100.0066.462080
HSA-MIR-6130100.0066.692012
HSA-MIR-6133100.0066.482064
HSA-MIR-4747-5P100.0067.902681
HSA-MIR-5196-5P100.0067.982761
HSA-MIR-33A-5P99.9968.621055
HSA-MIR-33B-5P99.9968.581062
HSA-MIR-607799.9968.042299
HSA-MIR-548C-3P99.9974.017587
HSA-MIR-1213699.9872.815713
HSA-MIR-548N99.9871.944170
HSA-MIR-6778-3P99.9667.292693
HSA-MIR-211099.9666.681930
HSA-MIR-1-3P99.9372.351914
HSA-MIR-20699.9372.501893
HSA-MIR-218-5P99.9372.222103
HSA-MIR-335-3P99.9373.364958
HSA-MIR-205-3P99.9269.923165
HSA-MIR-61399.9171.501710
HSA-MIR-374A-5P99.9071.342923
HSA-MIR-374B-5P99.9069.982734
HSA-MIR-990299.8969.152250
HSA-MIR-95-5P99.8972.173973

Literature-anchored findings (GeneRIF, showing 2)

  • METTL21A trimethylates Lys-561 in Hsp70 and corresponding residues in other isoforms (Hsc70, BiP) (PMID:23349634)
  • methyltransferase METTL21A is the enzyme responsible for trimethylation of a conserved lysine residue found in several human Hsp70 (HSPA) proteins (PMID:23921388)

Cross-species orthologs

3 orthologs

OrganismSymbolGene ID
danio_reriomettl21aENSDARG00000012051
mus_musculusMettl21aENSMUSG00000025956
rattus_norvegicusMettl21aENSRNOG00000014212

Paralogs (5): VCPKMT (ENSG00000100483), EEF1AKMT3 (ENSG00000123427), METTL21C (ENSG00000139780), METTL23 (ENSG00000181038), METTL21EP (ENSG00000250878)

Protein

Protein identifiers

Protein N-lysine methyltransferase METTL21AQ8WXB1 (reviewed: Q8WXB1)

Alternative names: HSPA lysine methyltransferase, HSPA-KMT, Hepatocellular carcinoma-associated antigen 557b, Methyltransferase-like protein 21A

All UniProt accessions (4): Q8WXB1, C9JES0, C9JSX1, H7BXH9

UniProt curated annotations — full annotation on UniProt →

Function. Protein-lysine methyltransferase that selectively trimethylates residues in heat shock protein 70 (HSP70) family members. Contributes to the in vivo trimethylation of Lys residues in HSPA1 and HSPA8. In vitro methylates ‘Lys-561’ in HSPA1, ‘Lys-564’ in HSPA2, ‘Lys-585’ in HSPA5, ‘Lys-563’ in HSPA6 and ‘Lys-561’ in HSPA8.

Subunit / interactions. Interacts with heat shock protein 70 family members; at least some of these proteins are methylation substrates.

Subcellular location. Cytoplasm.

Similarity. Belongs to the methyltransferase superfamily. METTL21 family.

Isoforms (2)

UniProt IDNamesCanonical?
Q8WXB1-11yes
Q8WXB1-22

RefSeq proteins (25): NP_001120867, NP_001294950, NP_001317059, NP_001317060, NP_001317061, NP_001317062, NP_001317063, NP_001317064, NP_001317065, NP_001317066, NP_001375356, NP_001375368, NP_001380492, NP_001380493, NP_001380494, NP_001380495, NP_001380496, NP_001380498, NP_001380499, NP_001380500, NP_001380501, NP_001380502, NP_001380503, NP_001380504, NP_660323 (=MANE)

Domains & families (InterPro)

IDNameType
IPR019410Methyltransf_16Family
IPR029063SAM-dependent_MTases_sfHomologous_superfamily

Pfam: PF10294

Catalyzed reactions (Rhea), 1 shown:

  • L-lysyl-[protein] + 3 S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl-[protein] + 3 S-adenosyl-L-homocysteine + 3 H(+) (RHEA:54192)

UniProt features (32 total): helix 10, strand 9, binding site 5, turn 2, splice variant 2, chain 1, sequence conflict 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDBMethodResolution (Å)
4LECX-RAY DIFFRACTION2.28

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q8WXB1-F191.570.85

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (5): 47; 73–75; 94; 125; 143

Mutagenesis-validated functional residues (1):

PositionPhenotype
94abolishes methyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

IDPathway
R-HSA-8876725Protein methylation
R-HSA-392499Metabolism of proteins
R-HSA-597592Post-translational protein modification

MSigDB gene sets: 140 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE45365_NK_CELL_VS_CD8A_DC_DN, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_PROTEIN_MATURATION, BILD_E2F3_ONCOGENIC_SIGNATURE, GOBP_PROTEIN_FOLDING, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_METHYLATION, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, LEE_RECENT_THYMIC_EMIGRANT, GOMF_HEAT_SHOCK_PROTEIN_BINDING, GOMF_N_METHYLTRANSFERASE_ACTIVITY, GOMF_PROTEIN_METHYLTRANSFERASE_ACTIVITY, GOMF_ATPASE_BINDING, GOMF_PROTEIN_FOLDING_CHAPERONE_BINDING

GO Biological Process (3): protein methylation (GO:0006479), negative regulation of protein folding (GO:1903333), methylation (GO:0032259)

GO Molecular Function (8): protein methyltransferase activity (GO:0008276), protein-lysine N-methyltransferase activity (GO:0016279), Hsp70 protein binding (GO:0030544), heat shock protein binding (GO:0031072), ATPase binding (GO:0051117), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytosol (GO:0005829), protein-containing complex (GO:0032991), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

CategoryPathways
Post-translational protein modification1
Metabolism of proteins1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
cellular anatomical structure3
protein alkylation1
macromolecule methylation1
protein folding1
negative regulation of cellular process1
regulation of protein folding1
metabolic process1
methyltransferase activity1
catalytic activity, acting on a protein1
protein methyltransferase activity1
lysine N-methyltransferase activity1
heat shock protein binding1
protein-folding chaperone binding1
protein binding1
enzyme binding1
binding1
transferase activity, transferring one-carbon groups1
catalytic activity1
nuclear lumen1
cytoplasm1
cellular_component1
intracellular anatomical structure1

Protein interactions and networks

STRING

562 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
METTL21AMETTL22Q9BUU2797
METTL21AMETTL18O95568735
METTL21AEEF1AKMT2Q5JPI9735
METTL21AETFBKMTQ8IXQ9716
METTL21AKINO60870687
METTL21AEEF2KMTQ96G04674
METTL21AEEF1AKMT1Q8WVE0666
METTL21ACAMKMTQ7Z624649
METTL21ACCNYL1Q8N7R7565
METTL21ANTMT1Q9BV86537
METTL21AMETTL13Q8N6R0536
METTL21AVCPP55072519
METTL21ACSKMTA8MUP2501
METTL21AEEF1AKMT4P0DPD7500
METTL21AANTKMTQ9BQD7489

IntAct

47 interactions, top by confidence:

ABTypeScore
METTL21AFAM200Cpsi-mi:“MI:0915”(physical association)0.740
FAM200CMETTL21Apsi-mi:“MI:0915”(physical association)0.740
LNX1METTL21Apsi-mi:“MI:0915”(physical association)0.670
METTL21ALNX1psi-mi:“MI:0915”(physical association)0.670
ATRIPMETTL21Apsi-mi:“MI:0915”(physical association)0.560
METTL21AATRIPpsi-mi:“MI:0915”(physical association)0.560
ZNF655METTL21Apsi-mi:“MI:0915”(physical association)0.560
METTL21AZNF620psi-mi:“MI:0915”(physical association)0.560
METTL21AMEI4psi-mi:“MI:0915”(physical association)0.560
METTL21AZNF655psi-mi:“MI:0915”(physical association)0.560
METTL21ALZTS1psi-mi:“MI:0915”(physical association)0.560
MEOX2METTL21Apsi-mi:“MI:0915”(physical association)0.560
METTL21AZRANB1psi-mi:“MI:0915”(physical association)0.560
METTL21APFDN5psi-mi:“MI:0915”(physical association)0.560
MSRB3METTL21Apsi-mi:“MI:0915”(physical association)0.560
ZNF620METTL21Apsi-mi:“MI:0915”(physical association)0.560
MEI4METTL21Apsi-mi:“MI:0915”(physical association)0.560
ARPC4METTL21Apsi-mi:“MI:0915”(physical association)0.560
METTL21ABAG3psi-mi:“MI:0914”(association)0.530
hspa1a_hspa1b_human-1SHTN1psi-mi:“MI:0914”(association)0.350
METTL21ABAG2psi-mi:“MI:0914”(association)0.350
METTL21AHSPA4Lpsi-mi:“MI:0914”(association)0.350

BioGRID (56): METTL21A (Two-hybrid), METTL21A (Two-hybrid), HSPA8 (Affinity Capture-MS), HSPA4 (Affinity Capture-MS), ZBED8 (Two-hybrid), HSPA8 (Affinity Capture-MS), HSPBP1 (Affinity Capture-MS), BAG3 (Affinity Capture-MS), HSPA4 (Affinity Capture-MS), SSA1 (Biochemical Activity), SSA3 (Biochemical Activity), HSPA8 (Biochemical Activity), METTL21A (Two-hybrid), METTL21A (Two-hybrid), METTL21A (Two-hybrid)

ESM2 similar proteins: A2RU49, A3KCL7, A4FV42, A7MBI7, A7RDN6, D3ZDM7, D3ZLY0, O88587, O95671, P11172, P13439, P13676, P13798, P17256, P21964, P22734, P25409, P31228, P31754, P51175, P80227, Q03426, Q0V8R7, Q14CH1, Q29RU9, Q3TY86, Q4JIJ2, Q5E9T8, Q5H879, Q5R514, Q5U2W9, Q6GM82, Q86TI2, Q86WA6, Q8BGT5, Q8BVG4, Q8QZR5, Q8R164, Q8WXB1, Q922Z0

Diamond homologs: A2AA28, A4FV42, A4FV98, A4IGU3, D3YWP0, O14118, Q28IN4, Q5BLD8, Q5RE14, Q5RJL2, Q6DJF8, Q86XA0, Q8CDZ2, Q8WXB1, Q96AZ1, Q9CQL0, A6NDL7, A6QP81, A7IQW5, P0CU27, P53970, Q2KIJ2, Q58DC7, Q5VZV1, Q8BLU2, Q8C436, Q8R1C6, Q9BUU2, Q9H867, F4JNX3, O95568, P40389, P47163, Q4KM84, Q55DL2, Q9CZ09, Q7S634, P0CP44, P0CP45, P64840

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

30 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance25
Likely benign0
Benign0

Top pathogenic / likely-pathogenic (0)

SpliceAI

964 predictions. Top by Δscore:

VariantEffectΔscore
2:207625060:ACC:Adonor_gain1.0000
2:207625061:CCC:Cdonor_gain1.0000
2:207625090:T:TAdonor_gain1.0000
2:207613056:T:TAdonor_gain0.9900
2:207624224:CTTA:Cdonor_gain0.9900
2:207624225:TTA:Tdonor_loss0.9900
2:207624226:TACCG:Tdonor_loss0.9900
2:207624227:A:ACdonor_gain0.9900
2:207624227:A:Cdonor_loss0.9900
2:207624228:C:CAdonor_loss0.9900
2:207624228:C:CCdonor_gain0.9900
2:207624228:CCG:Cdonor_gain0.9900
2:207624294:T:Cacceptor_gain0.9900
2:207624294:T:TCacceptor_gain0.9900
2:207625061:CCCCT:Cdonor_gain0.9900
2:207596912:A:AGacceptor_gain0.9800
2:207596912:AG:Aacceptor_gain0.9800
2:207596913:G:GGacceptor_gain0.9800
2:207596913:GG:Gacceptor_gain0.9800
2:207621804:AC:Adonor_gain0.9800
2:207621805:CC:Cdonor_gain0.9800
2:207624403:ACCTG:Aacceptor_loss0.9800
2:207624404:CCTGC:Cacceptor_loss0.9800
2:207624405:CTGC:Cacceptor_loss0.9800
2:207624406:T:Aacceptor_loss0.9800
2:207625060:AC:Adonor_gain0.9800
2:207625061:CC:Cdonor_gain0.9800
2:207625170:AGGAT:Adonor_gain0.9800
2:207596908:TTGTA:Tacceptor_loss0.9700
2:207596909:TGTA:Tacceptor_loss0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000146686 (2:207598956 C>G,T), RS1000180340 (2:207621257 A>T), RS1000195748 (2:207620975 A>G), RS1000408351 (2:207614759 A>T), RS1000480716 (2:207619164 A>G), RS1000502749 (2:207586319 A>G), RS1000512868 (2:207619586 C>T), RS1000793142 (2:207612972 A>G), RS1000804015 (2:207591328 C>G,T), RS1000888066 (2:207584847 T>G), RS1000954407 (2:207625502 C>A,G,T), RS1001006886 (2:207625794 G>A), RS1001067516 (2:207592545 T>C), RS1001168967 (2:207591427 GTTTTGT>G), RS1001253481 (2:207584513 C>G,T)

Disease associations

OMIM: gene MIM:615257 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

StudyTraitp-value
GCST001751_1Opioid sensitivity8.000000e-07
GCST002337_115Amyotrophic lateral sclerosis (sporadic)2.000000e-07
GCST004279_34Systolic blood pressure6.000000e-16
GCST004776_34Systolic blood pressure9.000000e-11
GCST004776_84Systolic blood pressure1.000000e-07
GCST007267_294Systolic blood pressure1.000000e-10
GCST010242_253HDL cholesterol levels1.000000e-09

EFO canonical traits (2, from GWAS)

EFO IDTrait name
EFO:0006335systolic blood pressure
EFO:0004612high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3588741 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

VariantTypeLevelDrugsPhenotypes
rs7569963Efficacy,Toxicity3antidepressants;citalopramDepression

PharmGKB variants

1 variants.

VariantGenesLevelScore#Clin annotsDrugs
rs7569963CREB1, METTL21A35.001antidepressants;citalopram

CTD chemical–gene interactions

42 total (human), top 30 by PubMed support.

ChemicalActions (top 5)PubMed papers
Valproic Acidaffects cotreatment, decreases expression, affects expression6
trichostatin Aaffects cotreatment, decreases expression2
Phenylmercuric Acetateaffects cotreatment, decreases expression2
Tetrachlorodibenzodioxindecreases expression2
aristolochic acid Idecreases expression1
bisphenol Aaffects cotreatment, decreases expression1
beta-lapachonedecreases expression1
sodium arsenitedecreases expression1
butyraldehydeincreases expression1
hydroquinonedecreases expression1
avobenzoneincreases expression1
entinostataffects cotreatment, decreases expression1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamideaffects cotreatment, decreases expression1
erucylphospho-N,N,N-trimethylpropylammoniumincreases expression1
ICG 001increases expression1
dorsomorphinaffects cotreatment, decreases expression1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidinedecreases expression, increases response to substance1
bisphenol Saffects cotreatment, decreases expression1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acidincreases expression1
Bortezomibincreases expression1
Temozolomidedecreases expression1
Panobinostataffects cotreatment, decreases expression1
Acetaminophenincreases expression1
Arsenicaffects methylation1
Caffeinedecreases phosphorylation1
Dexamethasoneaffects cotreatment, decreases expression1
Ethyl Methanesulfonatedecreases expression1
Gasolineaffects cotreatment, increases abundance, increases expression1
Hydrogen Peroxideaffects expression1
Indomethacinaffects cotreatment, decreases expression1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL3592419BindingInhibition of METTL21A (unknown origin) assessed as incorporation of tritium labeled methyl group from [3H]-SAM to substrate at 1 uM after 1 hr by scintillation proximity assay relative to controlDiscovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2. — ACS Med Chem Lett

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.