O94874 · UFL1_HUMAN
- ProteinE3 UFM1-protein ligase 1
- GeneUFL1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids794 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
E3 protein ligase that mediates ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to lysine residues on target proteins, and which plays a key role in various processes, such as ribosome recycling, response to DNA damage, interferon response or reticulophagy (also called ER-phagy) (PubMed:20018847, PubMed:20164180, PubMed:20228063, PubMed:25219498, PubMed:27351204, PubMed:30626644, PubMed:30783677, PubMed:32160526, PubMed:32807901, PubMed:35394863, PubMed:36121123, PubMed:36543799, PubMed:36893266, PubMed:37036982, PubMed:37311461, PubMed:37595036, PubMed:37795761, PubMed:38377992, PubMed:38383785, PubMed:38383789).
Catalyzes ufmylation of many protein, such as CD274/PD-L1, CDK5RAP3, CYB5R3, DDRGK1, EIF6, histone H4, MRE11, P4HB, PDCD1/PD-1, TRIP4, RPN1, RPS20/uS10, RPL10/uL16, RPL26/uL24, SYVN1/HRD1 and TP53/p53 (PubMed:20018847, PubMed:20531390, PubMed:25219498, PubMed:30783677, PubMed:30886146, PubMed:32160526, PubMed:35753586, PubMed:36543799, PubMed:36893266, PubMed:37036982, PubMed:37595036, PubMed:37795761, PubMed:38383785, PubMed:38383789).
As part of the UREL complex, plays a key role in ribosome recycling by catalyzing mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome (PubMed:38383785, PubMed:38383789).
Ufmylation of RPL26/uL24 occurs on free 60S ribosomes following ribosome dissociation: it weakens the junction between post-termination 60S subunits and SEC61 translocons, promoting release and recycling of the large ribosomal subunit from the endoplasmic reticulum membrane (PubMed:38383785, PubMed:38383789).
Ufmylation of RPL26/uL24 and subsequent 60S ribosome recycling either take place after normal termination of translation or after ribosome stalling during cotranslational translocation at the endoplasmic reticulum (PubMed:37036982, PubMed:37595036, PubMed:38383785, PubMed:38383789).
Involved in reticulophagy in response to endoplasmic reticulum stress by mediating ufmylation of proteins such as CYB5R3 and RPN1, thereby promoting lysosomal degradation of ufmylated proteins (PubMed:23152784, PubMed:32160526, PubMed:36543799).
Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis, blood vessel morphogenesis or inflammatory response (PubMed:32050156).
Mediates ufmylation of DDRGK1 and CDK5RAP3; the role of these modifications is however unclear: as both DDRGK1 and CDK5RAP3 act as substrate adapters for ufmylation, it is uncertain whether ufmylation of these proteins is, a collateral effect or is required for ufmylation (PubMed:20018847, PubMed:20531390).
Acts as a negative regulator of T-cell activation by mediating ufmylation and stabilization of PDCD1/PD-1 (PubMed:38377992).
Also involved in the response to DNA damage: recruited to double-strand break sites following DNA damage and mediates monoufmylation of histone H4 and ufmylation of MRE11 (PubMed:30783677, PubMed:30886146).
Mediates ufmylation of TP53/p53, promoting its stability (PubMed:32807901).
Catalyzes ufmylation of TRIP4, thereby playing a role in nuclear receptor-mediated transcription (PubMed:25219498).
Required for hematopoietic stem cell function and hematopoiesis (By similarity).
Catalyzes ufmylation of many protein, such as CD274/PD-L1, CDK5RAP3, CYB5R3, DDRGK1, EIF6, histone H4, MRE11, P4HB, PDCD1/PD-1, TRIP4, RPN1, RPS20/uS10, RPL10/uL16, RPL26/uL24, SYVN1/HRD1 and TP53/p53 (PubMed:20018847, PubMed:20531390, PubMed:25219498, PubMed:30783677, PubMed:30886146, PubMed:32160526, PubMed:35753586, PubMed:36543799, PubMed:36893266, PubMed:37036982, PubMed:37595036, PubMed:37795761, PubMed:38383785, PubMed:38383789).
As part of the UREL complex, plays a key role in ribosome recycling by catalyzing mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome (PubMed:38383785, PubMed:38383789).
Ufmylation of RPL26/uL24 occurs on free 60S ribosomes following ribosome dissociation: it weakens the junction between post-termination 60S subunits and SEC61 translocons, promoting release and recycling of the large ribosomal subunit from the endoplasmic reticulum membrane (PubMed:38383785, PubMed:38383789).
Ufmylation of RPL26/uL24 and subsequent 60S ribosome recycling either take place after normal termination of translation or after ribosome stalling during cotranslational translocation at the endoplasmic reticulum (PubMed:37036982, PubMed:37595036, PubMed:38383785, PubMed:38383789).
Involved in reticulophagy in response to endoplasmic reticulum stress by mediating ufmylation of proteins such as CYB5R3 and RPN1, thereby promoting lysosomal degradation of ufmylated proteins (PubMed:23152784, PubMed:32160526, PubMed:36543799).
Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis, blood vessel morphogenesis or inflammatory response (PubMed:32050156).
Mediates ufmylation of DDRGK1 and CDK5RAP3; the role of these modifications is however unclear: as both DDRGK1 and CDK5RAP3 act as substrate adapters for ufmylation, it is uncertain whether ufmylation of these proteins is, a collateral effect or is required for ufmylation (PubMed:20018847, PubMed:20531390).
Acts as a negative regulator of T-cell activation by mediating ufmylation and stabilization of PDCD1/PD-1 (PubMed:38377992).
Also involved in the response to DNA damage: recruited to double-strand break sites following DNA damage and mediates monoufmylation of histone H4 and ufmylation of MRE11 (PubMed:30783677, PubMed:30886146).
Mediates ufmylation of TP53/p53, promoting its stability (PubMed:32807901).
Catalyzes ufmylation of TRIP4, thereby playing a role in nuclear receptor-mediated transcription (PubMed:25219498).
Required for hematopoietic stem cell function and hematopoiesis (By similarity).
GO annotations
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameE3 UFM1-protein ligase 1
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionO94874
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Recruited to double-strand breaks by the MRE11-RAD50-NBN (MRN) complex following DNA damage.
Keywords
- Cellular component
Disease & Variants
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 8 | Abolished interaction with E2-like enzyme UFC1. | ||||
Sequence: I → R | ||||||
Mutagenesis | 11-15 | Abolished interaction with E2-like enzyme UFC1. | ||||
Sequence: LAADF → RAADR | ||||||
Mutagenesis | 15 | Abolished interaction with E2-like enzyme UFC1. | ||||
Sequence: F → R | ||||||
Mutagenesis | 19 | Abolished interaction with E2-like enzyme UFC1. | ||||
Sequence: Q → R | ||||||
Mutagenesis | 27 | Abolished interaction with DDRGK1; when associated with A-32--A-39. | ||||
Sequence: L → A | ||||||
Mutagenesis | 32 | Does not affect UFM1 ligase activity. | ||||
Sequence: C → A | ||||||
Mutagenesis | 32-39 | Abolished interaction with DDRGK1; when associated with A-27. | ||||
Sequence: CIEIVNKL → AIEAVNKA | ||||||
Mutagenesis | 125-127 | Abolished interaction with UFC1, impairing E3 protein ligase activity and ability to regulate ATM activation. | ||||
Sequence: Missing | ||||||
Mutagenesis | 129 | Abolished interaction with CDK5RAP3; when associated with A-185, A-191, A-199 and A-251. | ||||
Sequence: D → A | ||||||
Natural variant | VAR_034037 | 137 | in dbSNP:rs28372909 | |||
Sequence: V → F | ||||||
Mutagenesis | 143 | Does not affect UFM1 ligase activity. | ||||
Sequence: C → A | ||||||
Mutagenesis | 185 | Abolished interaction with CDK5RAP3; when associated with A-129, A-191, A-199 and A-251. | ||||
Sequence: R → A | ||||||
Mutagenesis | 191 | Abolished interaction with CDK5RAP3; when associated with A-129, A-185, A-199 and A-251. | ||||
Sequence: R → A | ||||||
Mutagenesis | 199 | Abolished interaction with CDK5RAP3; when associated with A-129, A-185, A-191 and A-251. | ||||
Sequence: R → A | ||||||
Mutagenesis | 251 | Abolished interaction with CDK5RAP3; when associated with A-129, A-185, A-191 and A-199. | ||||
Sequence: R → A | ||||||
Mutagenesis | 300 | Does not affect UFM1 ligase activity. | ||||
Sequence: C → A | ||||||
Mutagenesis | 372 | Does not affect UFM1 ligase activity. | ||||
Sequence: C → A | ||||||
Mutagenesis | 462 | Impaired recruitment to double-strand break sites. | ||||
Sequence: S → A | ||||||
Mutagenesis | 536 | Abolished phosphorylation by AMPK, preventing interaction with YWHAG/14-3-3-gamma and promoting PDCD1/PD-1 ufmylation. | ||||
Sequence: T → A | ||||||
Mutagenesis | 536 | Mimics phosphorylation; leading to decreased PDCD1/PD-1 ufmylation. | ||||
Sequence: T → E |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 924 variants from UniProt as well as other sources including ClinVar and dbSNP.
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_0000050771 | 2-794 | UniProt | E3 UFM1-protein ligase 1 | |||
Sequence: ADAWEEIRRLAADFQRAQFAEATQRLSERNCIEIVNKLIAQKQLEVVHTLDGKEYITPAQISKEMRDELHVRGGRVNIVDLQQVINVDLIHIENRIGDIIKSEKHVQLVLGQLIDENYLDRLAEEVNDKLQESGQVTISELCKTYDLPGNFLTQALTQRLGRIISGHIDLDNRGVIFTEAFVARHKARIRGLFSAITRPTAVNSLISKYGFQEQLLYSVLEELVNSGRLRGTVVGGRQDKAVFVPDIYSRTQSTWVDSFFRQNGYLEFDALSRLGIPDAVSYIKKRYKTTQLLFLKAACVGQGLVDQVEASVEEAISSGTWVDIAPLLPTSLSVEDAAILLQQVMRAFSKQASTVVFSDTVVVSEKFINDCTELFRELMHQKAEKEMKNNPVHLITEEDLKQISTLESVSTSKKDKKDERRRKATEGSGSMRGGGGGNAREYKIKKVKKKGRKDDDSDDESQSSHTGKKKPEISFMFQDEIEDFLRKHIQDAPEEFISELAEYLIKPLNKTYLEVVRSVFMSSTTSASGTGRKRTIKDLQEEVSNLYNNIRLFEKGMKFFADDTQAALTKHLLKSVCTDITNLIFNFLASDLMMAVDDPAAITSEIRKKILSKLSEETKVALTKLHNSLNEKSIEDFISCLDSAAEACDIMVKRGDKKRERQILFQHRQALAEQLKVTEDPALILHLTSVLLFQFSTHSMLHAPGRCVPQIIAFLNSKIPEDQHALLVKYQGLVVKQLVSQSKKTGQGDYPLNNELDKEQEDVASTTRKELQELSSSIKDLVLKSRKSSVTEE | |||||||
Modified residue (large scale data) | 411 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 429 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 431 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 433 | UniProt | Omega-N-methylarginine | ||||
Sequence: R | |||||||
Modified residue | 458 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 458 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 462 | UniProt | Phosphoserine; by ATM | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 462 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 536 | UniProt | Phosphothreonine; by AMPK | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 777 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 778 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 790 | PRIDE | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Ubiquitinated, leading to its degradation by the proteasome (PubMed:20164180).
Interaction with CDK5RAP3 protects both proteins against ubiquitination and degradation via the proteasome (PubMed:20164180).
Interaction with CDK5RAP3 protects both proteins against ubiquitination and degradation via the proteasome (PubMed:20164180).
Phosphorylated at Ser-462 by ATM, enhancing protein ligase activity and promoting ATM activation in a positive feedback loop (PubMed:30886146).
Phosphorylation at Thr-536 by AMPK promotes its interaction with YWHAG/14-3-3-gamma, thereby preventing UFL1 association with PDCD1/PD-1 substrate (PubMed:38377992).
Phosphorylation at Thr-536 by AMPK promotes its interaction with YWHAG/14-3-3-gamma, thereby preventing UFL1 association with PDCD1/PD-1 substrate (PubMed:38377992).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Ubiquitously expressed, with a high expression in liver (at protein level) (PubMed:20018847).
Low expression in several invasive hepatocellular carcinomas, such Hep-G2, Hep 3B2.1-7, HLE and PLC (PubMed:20018847).
Low expression in several invasive hepatocellular carcinomas, such Hep-G2, Hep 3B2.1-7, HLE and PLC (PubMed:20018847).
Induction
Up-regulated by thapsigargin (PubMed:23152784).
Down-regulated in the failing hearts of patients with dilated cardiomyopathy (PubMed:23152784).
Down-regulated in the failing hearts of patients with dilated cardiomyopathy (PubMed:23152784).
Gene expression databases
Organism-specific databases
Interaction
Subunit
Catalytic component of the UFM1 ribosome E3 ligase (UREL) complex, composed of UFL1, DDRGK1 and CDK5RAP3 (PubMed:20018847, PubMed:20164180, PubMed:20228063, PubMed:25219498, PubMed:32160526, PubMed:36121123, PubMed:36543799, PubMed:37595036, PubMed:38383785, PubMed:38383789).
Interacts with E2-like enzyme UFC1 (PubMed:20018847, PubMed:30886146, PubMed:37988244, PubMed:38383789).
Interacts with RELA (PubMed:20164180).
Interacts with NBN; promoting recruitment to double-strand breaks following DNA damage (PubMed:30886146).
Interacts (when phosphorylated) with YWHAG/14-3-3-gamma; sequestering UFL1 and preventing its association with PDCD1/PD-1 substrate (PubMed:38377992).
Interacts with E2-like enzyme UFC1 (PubMed:20018847, PubMed:30886146, PubMed:37988244, PubMed:38383789).
Interacts with RELA (PubMed:20164180).
Interacts with NBN; promoting recruitment to double-strand breaks following DNA damage (PubMed:30886146).
Interacts (when phosphorylated) with YWHAG/14-3-3-gamma; sequestering UFL1 and preventing its association with PDCD1/PD-1 substrate (PubMed:38377992).
(Microbial infection) Interacts with Epstein-Barr virus protein BILF1; this interaction mediates MAVS UFMylation and subsequent routing from mitochondria to lysosomes.
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | O94874 | CDK5RAP3 Q96JB5 | 11 | EBI-1048088, EBI-718818 | |
BINARY | O94874 | DDRGK1 Q96HY6 | 9 | EBI-1048088, EBI-1054024 | |
BINARY | O94874 | UFC1 Q9Y3C8 | 9 | EBI-1048088, EBI-1045733 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 2-200 | Mediates interaction with DDRGK1 | ||||
Sequence: ADAWEEIRRLAADFQRAQFAEATQRLSERNCIEIVNKLIAQKQLEVVHTLDGKEYITPAQISKEMRDELHVRGGRVNIVDLQQVINVDLIHIENRIGDIIKSEKHVQLVLGQLIDENYLDRLAEEVNDKLQESGQVTISELCKTYDLPGNFLTQALTQRLGRIISGHIDLDNRGVIFTEAFVARHKARIRGLFSAITRP | ||||||
Region | 2-212 | Required for E3 UFM1-protein ligase activity | ||||
Sequence: ADAWEEIRRLAADFQRAQFAEATQRLSERNCIEIVNKLIAQKQLEVVHTLDGKEYITPAQISKEMRDELHVRGGRVNIVDLQQVINVDLIHIENRIGDIIKSEKHVQLVLGQLIDENYLDRLAEEVNDKLQESGQVTISELCKTYDLPGNFLTQALTQRLGRIISGHIDLDNRGVIFTEAFVARHKARIRGLFSAITRPTAVNSLISKYGF | ||||||
Region | 121-250 | Involved in CDK5RAP3-binding | ||||
Sequence: DRLAEEVNDKLQESGQVTISELCKTYDLPGNFLTQALTQRLGRIISGHIDLDNRGVIFTEAFVARHKARIRGLFSAITRPTAVNSLISKYGFQEQLLYSVLEELVNSGRLRGTVVGGRQDKAVFVPDIYS | ||||||
Region | 200-400 | Mediates interaction with TRIP4 | ||||
Sequence: PTAVNSLISKYGFQEQLLYSVLEELVNSGRLRGTVVGGRQDKAVFVPDIYSRTQSTWVDSFFRQNGYLEFDALSRLGIPDAVSYIKKRYKTTQLLFLKAACVGQGLVDQVEASVEEAISSGTWVDIAPLLPTSLSVEDAAILLQQVMRAFSKQASTVVFSDTVVVSEKFINDCTELFRELMHQKAEKEMKNNPVHLITEED | ||||||
Region | 407-473 | Disordered | ||||
Sequence: LESVSTSKKDKKDERRRKATEGSGSMRGGGGGNAREYKIKKVKKKGRKDDDSDDESQSSHTGKKKPE | ||||||
Compositional bias | 411-428 | Basic and acidic residues | ||||
Sequence: STSKKDKKDERRRKATEG | ||||||
Compositional bias | 449-473 | Basic and acidic residues | ||||
Sequence: KKKGRKDDDSDDESQSSHTGKKKPE | ||||||
Region | 490-684 | Mediates interaction with CDK5RAP3 | ||||
Sequence: IQDAPEEFISELAEYLIKPLNKTYLEVVRSVFMSSTTSASGTGRKRTIKDLQEEVSNLYNNIRLFEKGMKFFADDTQAALTKHLLKSVCTDITNLIFNFLASDLMMAVDDPAAITSEIRKKILSKLSEETKVALTKLHNSLNEKSIEDFISCLDSAAEACDIMVKRGDKKRERQILFQHRQALAEQLKVTEDPAL | ||||||
Region | 745-770 | Disordered | ||||
Sequence: KTGQGDYPLNNELDKEQEDVASTTRK | ||||||
Compositional bias | 755-769 | Basic and acidic residues | ||||
Sequence: NELDKEQEDVASTTR |
Sequence similarities
Belongs to the UFL1 family.
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 3 isoforms produced by Alternative splicing.
O94874-1
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
- Length794
- Mass (Da)89,595
- Last updated2005-06-21 v2
- ChecksumC6C1777455551991
O94874-2
- Name2
- Differences from canonical
- 1-65: Missing
O94874-3
- Name3
Sequence caution
Features
Showing features for alternative sequence, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_038759 | 1-65 | in isoform 2 | |||
Sequence: Missing | ||||||
Compositional bias | 411-428 | Basic and acidic residues | ||||
Sequence: STSKKDKKDERRRKATEG | ||||||
Compositional bias | 449-473 | Basic and acidic residues | ||||
Sequence: KKKGRKDDDSDDESQSSHTGKKKPE | ||||||
Alternative sequence | VSP_038760 | 508-509 | in isoform 3 | |||
Sequence: PL → QV | ||||||
Alternative sequence | VSP_038761 | 510-794 | in isoform 3 | |||
Sequence: Missing | ||||||
Compositional bias | 755-769 | Basic and acidic residues | ||||
Sequence: NELDKEQEDVASTTR |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AB018319 EMBL· GenBank· DDBJ | BAA34496.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AK295934 EMBL· GenBank· DDBJ | BAG58719.1 EMBL· GenBank· DDBJ | mRNA | ||
AL132776 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
AL590404 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471051 EMBL· GenBank· DDBJ | EAW48507.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC015377 EMBL· GenBank· DDBJ | AAH15377.1 EMBL· GenBank· DDBJ | mRNA | Sequence problems. | |
BC028608 EMBL· GenBank· DDBJ | AAH28608.1 EMBL· GenBank· DDBJ | mRNA | ||
BC036379 EMBL· GenBank· DDBJ | AAH36379.1 EMBL· GenBank· DDBJ | mRNA |