EEF1AKMT3

Summary

EEF1AKMT3 (EEF1A lysine methyltransferase 3, HGNC:24936) is a protein-coding gene on chromosome 12q14.1, encoding EEF1A lysine methyltransferase 3 (Q96AZ1). Protein-lysine methyltransferase that selectively mono-, di- and trimethylates ‘Lys-165’ of the translation elongation factors EEF1A1 and EEF1A2 in an aminoacyl-tRNA and GTP-dependent manner.

Enables heat shock protein binding activity and protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine methylation. Located in several cellular components, including centrosome; chromosome; and nucleoplasm. Part of protein-containing complex.

Source: NCBI Gene 25895 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 47 total
• MANE Select transcript: NM_015433

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24936
Approved symbol	EEF1AKMT3
Name	EEF1A lysine methyltransferase 3
Location	12q14.1
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP586D0919
Ensembl gene	ENSG00000123427
Ensembl biotype	protein_coding
OMIM	615258
Entrez	25895

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000300209, ENST00000333012, ENST00000548256, ENST00000551420, ENST00000552307

RefSeq mRNA: 2 — MANE Select: NM_015433 NM_015433, NM_206914

CCDS: CCDS31848, CCDS8957

Canonical transcript exons

ENST00000300209 — 3 exons

Exon	Start	End
ENSE00002301479	57772614	57772901
ENSE00002393444	57780255	57782541
ENSE00003631087	57773017	57773128

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 88.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.8901 / max 191.2011, expressed in 1574 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126328	3.3623	1520
126329	0.5279	263

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	88.85	gold quality
sperm	CL:0000019	86.13	gold quality
pancreas	UBERON:0001264	84.12	gold quality
male germ cell	CL:0000015	83.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.24	gold quality
parotid gland	UBERON:0001831	81.52	gold quality
endocervix	UBERON:0000458	80.90	gold quality
adult mammalian kidney	UBERON:0000082	80.60	gold quality
right ovary	UBERON:0002118	80.39	gold quality
saliva-secreting gland	UBERON:0001044	80.22	gold quality
left ovary	UBERON:0002119	79.91	gold quality
descending thoracic aorta	UBERON:0002345	79.90	gold quality
body of uterus	UBERON:0009853	79.78	gold quality
stromal cell of endometrium	CL:0002255	79.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.54	gold quality
corpus epididymis	UBERON:0004359	79.54	gold quality
metanephros cortex	UBERON:0010533	79.34	gold quality
minor salivary gland	UBERON:0001830	79.30	gold quality
popliteal artery	UBERON:0002250	79.29	gold quality
tibial artery	UBERON:0007610	79.28	gold quality
right coronary artery	UBERON:0001625	79.08	gold quality
aorta	UBERON:0000947	78.93	gold quality
thoracic aorta	UBERON:0001515	78.73	gold quality
ectocervix	UBERON:0012249	78.73	gold quality
ascending aorta	UBERON:0001496	78.66	gold quality
left adrenal gland cortex	UBERON:0035825	78.51	gold quality
right uterine tube	UBERON:0001302	78.45	gold quality
ovary	UBERON:0000992	78.39	gold quality
left adrenal gland	UBERON:0001234	78.32	gold quality
body of stomach	UBERON:0001161	77.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.21

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

83 targeting EEF1AKMT3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-133A-3P	99.27	71.53	1270

Literature-anchored findings (GeneRIF, showing 4)

• The METTL21B protein is here suggested to be a protein methyltransferase, as it is shown to belong to a family of 10 human methyltransferases, some of which are shown to have lysine specific protein methyltransferase activity. (PMID:22948820)
• The present study identifies METTL21B as the enzyme responsible for methylation of eEF1A on Lys-165 and shows that this modification is dynamic, inducible and likely of regulatory importance. (PMID:28108655)
• Results have shown that METTL21B is a protein methyltransferase that methylates both isoforms of translation elongation factor eEF1A at lysine 165. Also, further data suggests that METTL21B has an evolutionarily important role for the methylation of lysine 165 in eEF1A. (PMID:28663172)
• METTL21B is a prognostic biomarker and potential therapeutic target in low-grade gliomas. (PMID:34446611)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Eef1akmt3	ENSMUSG00000080115
rattus_norvegicus	Eef1akmt3	ENSRNOG00000047631

Paralogs (5): VCPKMT (ENSG00000100483), METTL21C (ENSG00000139780), METTL21A (ENSG00000144401), METTL23 (ENSG00000181038), METTL21EP (ENSG00000250878)

Protein

Protein identifiers

EEF1A lysine methyltransferase 3 — Q96AZ1 (reviewed: Q96AZ1)

Alternative names: Hepatocellular carcinoma-associated antigen 557a, Methyltransferase-like protein 21B, Protein-lysine methyltransferase METTL21B, eEF1A-KMT3

All UniProt accessions (3): Q96AZ1, F8VZI8, F8W226

UniProt curated annotations — full annotation on UniProt →

Function. Protein-lysine methyltransferase that selectively mono-, di- and trimethylates ‘Lys-165’ of the translation elongation factors EEF1A1 and EEF1A2 in an aminoacyl-tRNA and GTP-dependent manner. EEF1A1 methylation by EEF1AKMT3 is dynamic as well as inducible by stress conditions, such as ER-stress, and plays a regulatory role on mRNA translation.

Subunit / interactions. Interacts with members of the heat shock protein 70 and 90 families and of the TCP-1 chaperonin family, as well as with HSPD1, STIP1 and tubulin; at least some of these proteins may be methylation substrates.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Similarity. Belongs to the methyltransferase superfamily. METTL21 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96AZ1-1	1	yes
Q96AZ1-2	2
Q96AZ1-3	3

RefSeq proteins (2): NP_056248, NP_996797 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019410	Methyltransf_16	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF10294

Catalyzed reactions (Rhea), 4 shown:

• L-lysyl-[protein] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:51736)
• 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)
• N(6)-methyl-L-lysyl-[protein] + S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:54196)
• N(6),N(6)-dimethyl-L-lysyl-[protein] + S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:54200)

UniProt features (33 total): helix 11, strand 9, binding site 5, splice variant 4, turn 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4QPN	X-RAY DIFFRACTION	1.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96AZ1-F1	91.21	0.85

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): 57; 83–85; 104; 133; 150

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 100 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, MENSE_HYPOXIA_UP, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_PEPTIDYL_LYSINE_MODIFICATION, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, GOCC_CENTROSOME, NIKOLSKY_BREAST_CANCER_12Q13_Q21_AMPLICON, MORF_RAP1A, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, GOBP_METHYLATION, MORF_MT4, GOBP_PEPTIDYL_LYSINE_METHYLATION, MORF_RFC1, GOMF_HEAT_SHOCK_PROTEIN_BINDING, GOMF_N_METHYLTRANSFERASE_ACTIVITY

GO Biological Process (2): peptidyl-lysine methylation (GO:0018022), methylation (GO:0032259)

GO Molecular Function (5): methyltransferase activity (GO:0008168), protein-lysine N-methyltransferase activity (GO:0016279), heat shock protein binding (GO:0031072), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (7): nucleoplasm (GO:0005654), chromosome (GO:0005694), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), protein-containing complex (GO:0032991), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular membraneless organelle	2
protein methylation	1
peptidyl-lysine modification	1
metabolic process	1
transferase activity, transferring one-carbon groups	1
protein methyltransferase activity	1
lysine N-methyltransferase activity	1
protein binding	1
binding	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cytoplasm	1
cellular_component	1

Protein interactions and networks

STRING

407 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EEF1AKMT3	EEF1AKMT1	Q8WVE0	685
EEF1AKMT3	EEF1AKMT2	Q5JPI9	664
EEF1AKMT3	METTL1	Q9UBP6	647
EEF1AKMT3	ETFBKMT	Q8IXQ9	628
EEF1AKMT3	METTL18	O95568	601
EEF1AKMT3	TSFM	P43897	542
EEF1AKMT3	CSKMT	A8MUP2	538
EEF1AKMT3	KIN	O60870	520
EEF1AKMT3	EEF1AKMT4	P0DPD7	513
EEF1AKMT3	ZC2HC1A	Q96GY0	506
EEF1AKMT3	METTL13	Q8N6R0	481
EEF1AKMT3	METTL25B	Q96FB5	474
EEF1AKMT3	AVIL	O75366	447
EEF1AKMT3	TSPAN31	Q12999	447
EEF1AKMT3	CYP27B1	O15528	433

IntAct

18 interactions, top by confidence:

A	B	Type	Score
ALS2CL	EEF1AKMT3	psi-mi:“MI:0915”(physical association)	0.560
ZIC1	EEF1AKMT3	psi-mi:“MI:0915”(physical association)	0.560
MSRB3	EEF1AKMT3	psi-mi:“MI:0915”(physical association)	0.560
MAGEB4	EEF1AKMT3	psi-mi:“MI:0915”(physical association)	0.560
VAC14	EEF1AKMT3	psi-mi:“MI:0915”(physical association)	0.560
METTL13	EEF1AKMT3	psi-mi:“MI:0915”(physical association)	0.560
EEF1AKMT3	SMCHD1	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT3	VAC14	psi-mi:“MI:0915”(physical association)	0.000
EEF1AKMT3	ALS2CL	psi-mi:“MI:0915”(physical association)	0.000
MSRB3	EEF1AKMT3	psi-mi:“MI:0915”(physical association)	0.000
ZIC1	EEF1AKMT3	psi-mi:“MI:0915”(physical association)	0.000
MAGEB4	EEF1AKMT3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (365): METTL21B (Two-hybrid), METTL21B (Two-hybrid), ZIC1 (Two-hybrid), MSRB3 (Two-hybrid), ALS2CL (Two-hybrid), METTL21B (Affinity Capture-RNA), OSBPL3 (Affinity Capture-MS), CTR9 (Affinity Capture-MS), TTF2 (Affinity Capture-MS), NLRP2 (Affinity Capture-MS), ANKHD1 (Affinity Capture-MS), ANKS1A (Affinity Capture-MS), CHD1L (Affinity Capture-MS), RGL3 (Affinity Capture-MS), POLD1 (Affinity Capture-MS)

ESM2 similar proteins: A2AA28, A2RRH5, A4FV42, A6NDL7, A7MCT6, B0K012, B2RYG8, D3YWP0, D3ZRW8, E1B8U2, J3S6Y1, P21964, P50747, Q0V8R7, Q1JP61, Q2TBI8, Q3SZD4, Q3U2J5, Q4VBE8, Q58DC7, Q5E9Y6, Q5RJL2, Q5VZV1, Q6DJF8, Q6GQ33, Q6P9U1, Q7Z624, Q80WC9, Q86XA0, Q8BNV1, Q8C436, Q8CDZ2, Q8IZ69, Q8N371, Q8R1C6, Q8WU66, Q920N2, Q96AZ1, Q96CB9, Q96RR1

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1106 predictions. Top by Δscore:

Variant	Effect	Δscore
12:57771955:C:CA	donor_gain	1.0000
12:57771972:A:AC	donor_gain	1.0000
12:57771973:C:CC	donor_gain	1.0000
12:57771973:CTAG:C	donor_gain	1.0000
12:57772459:ACT:A	donor_gain	1.0000
12:57772460:CTC:C	donor_gain	1.0000
12:57772710:C:CA	donor_gain	1.0000
12:57772779:G:GT	donor_gain	1.0000
12:57772779:G:T	donor_gain	1.0000
12:57773127:GG:G	donor_gain	1.0000
12:57773128:GG:G	donor_gain	1.0000
12:57771965:A:AC	donor_gain	0.9900
12:57771965:ACT:A	donor_gain	0.9900
12:57771966:C:CC	donor_gain	0.9900
12:57771966:CTC:C	donor_gain	0.9900
12:57771981:G:C	donor_gain	0.9900
12:57772017:G:A	donor_gain	0.9900
12:57772339:G:C	donor_gain	0.9900
12:57772459:A:AC	donor_gain	0.9900
12:57772460:C:CC	donor_gain	0.9900
12:57772753:C:G	donor_gain	0.9900
12:57772821:T:G	donor_gain	0.9900
12:57772899:GCG:G	donor_gain	0.9900
12:57773011:CCGTA:C	acceptor_loss	0.9900
12:57773012:CGTA:C	acceptor_loss	0.9900
12:57773013:GTAG:G	acceptor_loss	0.9900
12:57773014:TA:T	acceptor_loss	0.9900
12:57773015:A:AG	acceptor_gain	0.9900
12:57773015:AGGCC:A	acceptor_loss	0.9900
12:57773016:G:GG	acceptor_gain	0.9900

AlphaMissense

1470 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:57780362:T:A	W133R	0.998
12:57780362:T:C	W133R	0.998
12:57780364:G:C	W133C	0.997
12:57780364:G:T	W133C	0.997
12:57772893:T:A	W57R	0.996
12:57772893:T:C	W57R	0.996
12:57772895:G:C	W57C	0.995
12:57772895:G:T	W57C	0.995
12:57773107:G:T	G90W	0.995
12:57780273:C:T	T103I	0.995
12:57773099:G:A	G87D	0.994
12:57780276:A:C	D104A	0.994
12:57780417:A:T	D151V	0.994
12:57780275:G:C	D104H	0.993
12:57780276:A:T	D104V	0.993
12:57780411:G:A	G149E	0.993
12:57773093:G:T	G85V	0.992
12:57773099:G:T	G87V	0.992
12:57773107:G:A	G90R	0.992
12:57773107:G:C	G90R	0.992
12:57780276:A:G	D104G	0.992
12:57780363:G:C	W133S	0.992
12:57773030:G:A	C64Y	0.991
12:57773089:G:C	A84P	0.991
12:57773092:G:T	G85W	0.991
12:57773108:G:A	G90E	0.991
12:57780413:G:C	A150P	0.991
12:57780416:G:C	D151H	0.991
12:57780310:C:A	N115K	0.990
12:57780310:C:G	N115K	0.990

dbSNP variants (sampled 300 via entrez): RS1000322606 (12:57775910 A>C), RS1000565826 (12:57782764 A>C,G), RS1001216002 (12:57775220 G>A,C,T), RS1001268407 (12:57775003 G>A), RS1001560408 (12:57776501 C>T), RS1002220579 (12:57776758 C>G), RS1002883733 (12:57782454 A>G), RS1003098086 (12:57779156 T>C), RS1003558669 (12:57779959 G>A), RS1003559139 (12:57774064 T>C), RS1004226581 (12:57780411 G>T), RS1004389212 (12:57781763 A>G), RS1004747086 (12:57782196 T>C), RS1004939916 (12:57776354 C>T), RS1005187492 (12:57778579 T>C)

Disease associations

OMIM: gene MIM:615258 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010703_209	Brain morphology (MOSTest)	2.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation, increases methylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	increases expression	1
Leflunomide	decreases expression	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Arsenic	affects methylation	1
Cisplatin	increases expression	1
Estradiol	increases expression	1
Gasoline	increases abundance, affects cotreatment, decreases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Quercetin	increases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Thimerosal	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	increases expression	1
Sodium Selenite	decreases expression	1
Okadaic Acid	decreases expression	1
Particulate Matter	affects cotreatment, decreases expression, increases abundance	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SX99	HAP1 METTL21B (-) 1	Cancer cell line	Male
CVCL_SY00	HAP1 METTL21B (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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