P57081 · WDR4_HUMAN
- ProteintRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4
- GeneWDR4
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids412 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Non-catalytic component of the METTL1-WDR4 methyltransferase complex required for the formation of N7-methylguanine in a subset of RNA species, such as tRNAs, mRNAs and microRNAs (miRNAs) (PubMed:12403464, PubMed:31031083, PubMed:31031084, PubMed:36599982, PubMed:36599985, PubMed:37369656).
In the METTL1-WDR4 methyltransferase complex, WDR4 acts as a scaffold for tRNA-binding (PubMed:36599982, PubMed:36599985, PubMed:37369656).
Required for the formation of N7-methylguanine at position 46 (m7G46) in a large subset of tRNAs that contain the 5'-RAGGU-3' motif within the variable loop (PubMed:12403464, PubMed:34352206, PubMed:34352207, PubMed:36599982, PubMed:36599985, PubMed:37369656).
M7G46 interacts with C13-G22 in the D-loop to stabilize tRNA tertiary structure and protect tRNAs from decay (PubMed:36599982, PubMed:36599985).
Also required for the formation of N7-methylguanine at internal sites in a subset of mRNAs (PubMed:31031084, PubMed:37379838).
Also required for methylation of a specific subset of miRNAs, such as let-7 (PubMed:31031083).
Independently of METTL1, also plays a role in genome stability: localizes at the DNA replication site and regulates endonucleolytic activities of FEN1 (PubMed:26751069).
In the METTL1-WDR4 methyltransferase complex, WDR4 acts as a scaffold for tRNA-binding (PubMed:36599982, PubMed:36599985, PubMed:37369656).
Required for the formation of N7-methylguanine at position 46 (m7G46) in a large subset of tRNAs that contain the 5'-RAGGU-3' motif within the variable loop (PubMed:12403464, PubMed:34352206, PubMed:34352207, PubMed:36599982, PubMed:36599985, PubMed:37369656).
M7G46 interacts with C13-G22 in the D-loop to stabilize tRNA tertiary structure and protect tRNAs from decay (PubMed:36599982, PubMed:36599985).
Also required for the formation of N7-methylguanine at internal sites in a subset of mRNAs (PubMed:31031084, PubMed:37379838).
Also required for methylation of a specific subset of miRNAs, such as let-7 (PubMed:31031083).
Independently of METTL1, also plays a role in genome stability: localizes at the DNA replication site and regulates endonucleolytic activities of FEN1 (PubMed:26751069).
Miscellaneous
In the context of cancer, overexpression of the METTL1-WDR4 methyltransferase complex promotes cancer progression by driving oncogenic transformation (PubMed:34352206, PubMed:34352207, PubMed:34371184).
The METTL1-WDR4 methyltransferase complex drives oncogenesis by mediating the formation of N7-methylguanine at position 46 (m7G46) in some tRNAs, in particular Arg-TCT-4-1 (TRR-TCT4-1), leading to increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon (PubMed:34352206, PubMed:34352207, PubMed:34371184).
The METTL1-WDR4 methyltransferase complex drives oncogenesis by mediating the formation of N7-methylguanine at position 46 (m7G46) in some tRNAs, in particular Arg-TCT-4-1 (TRR-TCT4-1), leading to increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon (PubMed:34352206, PubMed:34352207, PubMed:34371184).
Pathway
tRNA modification; N7-methylguanine-tRNA biosynthesis.
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | chromosome | |
Cellular Component | cytosol | |
Cellular Component | nucleoplasm | |
Cellular Component | nucleus | |
Cellular Component | tRNA (m7G46) methyltransferase complex | |
Cellular Component | tRNA methyltransferase complex | |
Molecular Function | enzyme activator activity | |
Molecular Function | tRNA methyltransferase activator activity | |
Biological Process | DNA damage response | |
Biological Process | tRNA (guanine-N7)-methylation | |
Biological Process | tRNA modification |
Keywords
- Biological process
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nametRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP57081
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Localizes at the site of nascent DNA synthesis.
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Galloway-Mowat syndrome 6 (GAMOS6)
- Note
- DescriptionA form of Galloway-Mowat syndrome, a severe renal-neurological disease characterized by early-onset nephrotic syndrome associated with microcephaly, central nervous system abnormalities, developmental delays, and a propensity for seizures. Brain anomalies include gyration defects ranging from lissencephaly to pachygyria and polymicrogyria, and cerebellar hypoplasia. Most patients show facial dysmorphism characterized by a small, narrow forehead, large/floppy ears, deep-set eyes, hypertelorism and micrognathia. Additional variable features are visual impairment and arachnodactyly. Most patients die in early childhood. GAMOS6 is an autosomal recessive form with onset in infancy or early childhood. Affected individuals manifest microcephaly, global developmental delay, variable degrees of intellectual disability, and growth deficiency. Renal impairment may be age-dependent or may not be present.
- See alsoMIM:618347
Natural variants in GAMOS6
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_081828 | 164 | D>A | in GAMOS6; uncertain significance; dbSNP:rs1555976610 | |
VAR_081830 | 170 | R>Q | in GAMOS6; abolished formation of N7-methylguanine in tRNAs; dbSNP:rs1292041526 |
Microcephaly, growth deficiency, seizures, and brain malformations (MIGSB)
- Note
- DescriptionAn autosomal recessive disorder characterized by intrauterine growth retardation, postnatal growth deficiency, microcephaly, facial dysmorphism, early-onset seizures, brain malformations such as partial agenesis of the corpus callosum and simplified gyration, and poor or absent psychomotor development.
- See alsoMIM:618346
Natural variants in MIGSB
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_081829 | 170 | R>L | in MIGSB; abolished formation of N7-methylguanine in tRNAs |
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_020120 | 71 | in dbSNP:rs2248490 | |||
Sequence: K → N | ||||||
Mutagenesis | 83 | Slightly reduced formation of N7-methylguanine in tRNAs. | ||||
Sequence: K → A | ||||||
Mutagenesis | 103 | Does not affect formation of N7-methylguanine in tRNAs. | ||||
Sequence: R → A | ||||||
Mutagenesis | 103-104 | Abolished formation of N7-methylguanine in tRNAs. | ||||
Sequence: RR → AA | ||||||
Mutagenesis | 104 | Does not affect formation of N7-methylguanine in tRNAs. | ||||
Sequence: R → A | ||||||
Mutagenesis | 122 | Does not affect formation of N7-methylguanine in tRNAs. | ||||
Sequence: K → A | ||||||
Natural variant | VAR_087852 | 144 | found in a patient with lung cancer; abolished formation of N7-methylguanine in tRNAs | |||
Sequence: H → P | ||||||
Mutagenesis | 147 | Reduced formation of N7-methylguanine in tRNAs. | ||||
Sequence: M → A | ||||||
Natural variant | VAR_081828 | 164 | in GAMOS6; uncertain significance; dbSNP:rs1555976610 | |||
Sequence: D → A | ||||||
Mutagenesis | 165 | Abolished formation of N7-methylguanine in tRNAs. | ||||
Sequence: R → A | ||||||
Mutagenesis | 166 | Abolished formation of N7-methylguanine in tRNAs. | ||||
Sequence: D → A | ||||||
Mutagenesis | 167 | Abolished formation of N7-methylguanine in tRNAs. | ||||
Sequence: E → A | ||||||
Natural variant | VAR_081829 | 170 | in MIGSB; abolished formation of N7-methylguanine in tRNAs | |||
Sequence: R → L | ||||||
Natural variant | VAR_081830 | 170 | in GAMOS6; abolished formation of N7-methylguanine in tRNAs; dbSNP:rs1292041526 | |||
Sequence: R → Q | ||||||
Mutagenesis | 170 | Reduced formation of N7-methylguanine in tRNAs. | ||||
Sequence: R → A | ||||||
Natural variant | VAR_033121 | 266 | in dbSNP:rs15736 | |||
Sequence: P → S | ||||||
Mutagenesis | 365 | Reduced formation of N7-methylguanine in tRNAs. | ||||
Sequence: F → A | ||||||
Mutagenesis | 371 | Slightly reduced formation of N7-methylguanine in tRNAs. | ||||
Sequence: Y → A | ||||||
Natural variant | VAR_033122 | 390 | in dbSNP:rs6586250 | |||
Sequence: R → Q |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 652 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Genetic variation databases
PTM/Processing
Features
Showing features for initiator methionine, modified residue, chain, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Initiator methionine | 1 | UniProt | Removed | ||||
Sequence: M | |||||||
Modified residue | 2 | UniProt | N-acetylalanine | ||||
Sequence: A | |||||||
Chain | PRO_0000051348 | 2-412 | UniProt | tRNA (guanine-N7-)-methyltransferase non-catalytic subunit WDR4 | |||
Sequence: AGSVGLALCGQTLVVRGGSRFLATSIASSDDDSLFIYDCSAAEKKSQENKGEDAPLDQGSGAILASTFSKSGSYFALTDDSKRLILFRTKPWQCLSVRTVARRCTALTFIASEEKVLVADKSGDVYSFSVLEPHGCGRLELGHLSMLLDVAVSPDDRFILTADRDEKIRVSWAAAPHSIESFCLGHTEFVSRISVVPTQPGLLLSSSGDGTLRLWEYRSGRQLHCCHLASLQELVDPQAPQKFAASRIAFWCQENCVALLCDGTPVVYIFQLDARRQQLVYRQQLAFQHQVWDVAFEETQGLWVLQDCQEAPLVLYRPVGDQWQSVPESTVLKKVSGVLRGNWAMLEGSAGADASFSSLYKATFDNVTSYLKKKEERLQQQLEKKQRRRSPPPGPDGHAKKMRPGEATLSC | |||||||
Modified residue | 391 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 391 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 411 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 411 | PRIDE | Phosphoserine | ||||
Sequence: S |
Keywords
- PTM
Proteomic databases
PTM databases
Interaction
Subunit
Non-catalytic component of the METTL1-WDR4 complex, composed of METTL1 and WDR4 (PubMed:12403464, PubMed:26751069, PubMed:36599982, PubMed:36599985, PubMed:37379838).
Interacts with FEN1; the interaction is direct (PubMed:26751069).
Interacts with FEN1; the interaction is direct (PubMed:26751069).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | P57081 | FAM118A Q9NWS6 | 7 | EBI-750427, EBI-8638992 | |
BINARY | P57081 | FEN1 P39748 | 8 | EBI-750427, EBI-707816 | |
BINARY | P57081 | METTL1 Q9UBP6 | 15 | EBI-750427, EBI-750415 | |
BINARY | P57081 | RABGGTB P53611 | 6 | EBI-750427, EBI-536715 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for repeat, compositional bias, region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Repeat | 3-40 | WD 1 | ||||
Sequence: GSVGLALCGQTLVVRGGSRFLATSIASSDDDSLFIYDC | ||||||
Repeat | 50-90 | WD 2 | ||||
Sequence: NKGEDAPLDQGSGAILASTFSKSGSYFALTDDSKRLILFRT | ||||||
Repeat | 94-131 | WD 3 | ||||
Sequence: QCLSVRTVARRCTALTFIASEEKVLVADKSGDVYSFSV | ||||||
Repeat | 137-174 | WD 4 | ||||
Sequence: CGRLELGHLSMLLDVAVSPDDRFILTADRDEKIRVSWA | ||||||
Repeat | 180-218 | WD 5 | ||||
Sequence: IESFCLGHTEFVSRISVVPTQPGLLLSSSGDGTLRLWEY | ||||||
Repeat | 230-273 | WD 6 | ||||
Sequence: ASLQELVDPQAPQKFAASRIAFWCQENCVALLCDGTPVVYIFQL | ||||||
Repeat | 319-373 | WD 7 | ||||
Sequence: PVGDQWQSVPESTVLKKVSGVLRGNWAMLEGSAGADASFSSLYKATFDNVTSYLK | ||||||
Compositional bias | 377-404 | Basic and acidic residues | ||||
Sequence: ERLQQQLEKKQRRRSPPPGPDGHAKKMR | ||||||
Region | 377-412 | Disordered | ||||
Sequence: ERLQQQLEKKQRRRSPPPGPDGHAKKMRPGEATLSC |
Sequence similarities
Belongs to the WD repeat TRM82 family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 3 isoforms produced by Alternative splicing.
P57081-1
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.
- Name1
- Length412
- Mass (Da)45,490
- Last updated2002-02-11 v2
- Checksum394B11A2AFB1CADB
P57081-2
- Name2
- Differences from canonical
- 243-243: Missing
P57081-3
- Name3
- Differences from canonical
- 1-146: Missing
Features
Showing features for alternative sequence, sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_036935 | 1-146 | in isoform 3 | |||
Sequence: Missing | ||||||
Sequence conflict | 141 | in Ref. 1; CAB93144/CAB93145 | ||||
Sequence: E → K | ||||||
Sequence conflict | 149 | in Ref. 1; CAB93144/CAB93145 | ||||
Sequence: L → V | ||||||
Sequence conflict | 236 | in Ref. 2; BAG37500 | ||||
Sequence: V → A | ||||||
Alternative sequence | VSP_036936 | 243 | in isoform 2 | |||
Sequence: Missing | ||||||
Sequence conflict | 318 | in Ref. 2; BAG60319 | ||||
Sequence: R → K | ||||||
Compositional bias | 377-404 | Basic and acidic residues | ||||
Sequence: ERLQQQLEKKQRRRSPPPGPDGHAKKMR |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AJ243912 EMBL· GenBank· DDBJ | CAB93144.1 EMBL· GenBank· DDBJ | mRNA | ||
AJ243913 EMBL· GenBank· DDBJ | CAB93145.1 EMBL· GenBank· DDBJ | mRNA | ||
AK056343 EMBL· GenBank· DDBJ | BAG51684.1 EMBL· GenBank· DDBJ | mRNA | ||
AK292923 EMBL· GenBank· DDBJ | BAF85612.1 EMBL· GenBank· DDBJ | mRNA | ||
AK298015 EMBL· GenBank· DDBJ | BAG60319.1 EMBL· GenBank· DDBJ | mRNA | ||
AK315008 EMBL· GenBank· DDBJ | BAG37500.1 EMBL· GenBank· DDBJ | mRNA | ||
AB039887 EMBL· GenBank· DDBJ | BAB13726.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AP001629 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471079 EMBL· GenBank· DDBJ | EAX09528.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471079 EMBL· GenBank· DDBJ | EAX09529.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC001074 EMBL· GenBank· DDBJ | AAH01074.1 EMBL· GenBank· DDBJ | mRNA | ||
BC006341 EMBL· GenBank· DDBJ | AAH06341.1 EMBL· GenBank· DDBJ | mRNA |