Q9GZZ9 · UBA5_HUMAN
- ProteinUbiquitin-like modifier-activating enzyme 5
- GeneUBA5
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids404 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
E1-like enzyme which specifically catalyzes the first step in ufmylation (PubMed:15071506, PubMed:18442052, PubMed:20368332, PubMed:25219498, PubMed:26929408, PubMed:27545674, PubMed:27545681, PubMed:27653677, PubMed:30412706, PubMed:30626644, PubMed:34588452).
Activates UFM1 by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a UFM1-E1 thioester and free AMP (PubMed:20368332, PubMed:26929408, PubMed:27653677, PubMed:30412706).
Activates UFM1 via a trans-binding mechanism, in which UFM1 interacts with distinct sites in both subunits of the UBA5 homodimer (PubMed:27653677).
Trans-binding also promotes stabilization of the UBA5 homodimer, and enhances ATP-binding (PubMed:29295865).
Transfer of UFM1 from UBA5 to the E2-like enzyme UFC1 also takes place using a trans mechanism (PubMed:27653677, PubMed:34588452).
Ufmylation plays a key role in various processes, such as ribosome recycling, response to DNA damage, interferon response or reticulophagy (also called ER-phagy) (PubMed:30412706, PubMed:32160526, PubMed:35394863).
Ufmylation is essential for erythroid differentiation of both megakaryocytes and erythrocytes (By similarity).
Activates UFM1 by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a UFM1-E1 thioester and free AMP (PubMed:20368332, PubMed:26929408, PubMed:27653677, PubMed:30412706).
Activates UFM1 via a trans-binding mechanism, in which UFM1 interacts with distinct sites in both subunits of the UBA5 homodimer (PubMed:27653677).
Trans-binding also promotes stabilization of the UBA5 homodimer, and enhances ATP-binding (PubMed:29295865).
Transfer of UFM1 from UBA5 to the E2-like enzyme UFC1 also takes place using a trans mechanism (PubMed:27653677, PubMed:34588452).
Ufmylation plays a key role in various processes, such as ribosome recycling, response to DNA damage, interferon response or reticulophagy (also called ER-phagy) (PubMed:30412706, PubMed:32160526, PubMed:35394863).
Ufmylation is essential for erythroid differentiation of both megakaryocytes and erythrocytes (By similarity).
Features
Showing features for binding site, active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 83 | ATP (UniProtKB | ChEBI) | ||||
Sequence: G | ||||||
Binding site | 104 | ATP (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 127 | ATP (UniProtKB | ChEBI) | ||||
Sequence: K | ||||||
Binding site | 150 | ATP (UniProtKB | ChEBI) | ||||
Sequence: N | ||||||
Binding site | 184 | ATP (UniProtKB | ChEBI) | ||||
Sequence: N | ||||||
Binding site | 226 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 229 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Active site | 250 | Glycyl thioester intermediate | ||||
Sequence: C | ||||||
Binding site | 303 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 308 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: C |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cytoplasm | |
Cellular Component | cytosol | |
Cellular Component | endoplasmic reticulum membrane | |
Cellular Component | Golgi apparatus | |
Cellular Component | intracellular membrane-bounded organelle | |
Cellular Component | nucleus | |
Molecular Function | ATP binding | |
Molecular Function | protein homodimerization activity | |
Molecular Function | UFM1 activating enzyme activity | |
Molecular Function | zinc ion binding | |
Biological Process | erythrocyte differentiation | |
Biological Process | megakaryocyte differentiation | |
Biological Process | neuromuscular process | |
Biological Process | protein K69-linked ufmylation | |
Biological Process | protein ufmylation | |
Biological Process | regulation of intracellular estrogen receptor signaling pathway | |
Biological Process | response to endoplasmic reticulum stress | |
Biological Process | reticulophagy |
Keywords
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameUbiquitin-like modifier-activating enzyme 5
- Short namesUbiquitin-activating enzyme 5
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ9GZZ9
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Developmental and epileptic encephalopathy 44 (DEE44)
- Note
- DescriptionA form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE44 transmission pattern is consistent with autosomal recessive inheritance.
- See alsoMIM:617132
Natural variants in DEE44
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_077153 | 55 | R>H | in DEE44; reduces UFM1 activating enzyme activity; dbSNP:rs774318611 | |
VAR_077154 | 57 | M>V | in DEE44; reduces UFM1 activating enzyme activity; reduces UFM1-DDRGK1 formation; dbSNP:rs532178791 | |
VAR_077155 | 168 | G>E | in DEE44; abolishes UFM1 activating enzyme activity; dbSNP:rs886039761 | |
VAR_077156 | 260 | V>M | in DEE44; reduces UFM1 activating enzyme activity; dbSNP:rs886039759 | |
VAR_077158 | 371 | A>T | in DEE44; reduces UFM1 activating enzyme activity; reduces UFM1 activating enzyme activity; reduces UFM1-DDRGK1 formation; dbSNP:rs114925667 | |
VAR_077159 | 389 | D>Y | in DEE44; no effect on UFM1 activating enzyme activity; dbSNP:rs886039760 |
Spinocerebellar ataxia, autosomal recessive, 24 (SCAR24)
- Note
- DescriptionA form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR24 patients manifest gait instability and speech difficulties with onset in childhood. Clinical features include gait and limb ataxia, dysarthria, nystagmus, cataracts, and cerebellar atrophy on brain imaging.
- See alsoMIM:617133
Natural variants in SCAR24
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_080409 | 246-404 | missing | in SCAR24; delocalizes protein to the nucleus; activates degradation through the ubiquitin proteasome pathway; decreases protein stability; disrupts interaction with UFM1 | |
VAR_077157 | 310 | K>E | in SCAR24; does not affect cytoplasm localization; decreases protein stability; does not affect interaction with UFM1; dbSNP:rs886039762 |
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_077153 | 55 | in DEE44; reduces UFM1 activating enzyme activity; dbSNP:rs774318611 | |||
Sequence: R → H | ||||||
Natural variant | VAR_077154 | 57 | in DEE44; reduces UFM1 activating enzyme activity; reduces UFM1-DDRGK1 formation; dbSNP:rs532178791 | |||
Sequence: M → V | ||||||
Natural variant | VAR_077155 | 168 | in DEE44; abolishes UFM1 activating enzyme activity; dbSNP:rs886039761 | |||
Sequence: G → E | ||||||
Mutagenesis | 188 | Abolished ability to activate UFM1. | ||||
Sequence: R → A | ||||||
Mutagenesis | 215-217 | Abolished ability to activate UFM1. | ||||
Sequence: HIQ → AQA | ||||||
Mutagenesis | 230-233 | Abolished interaction with UFM1. | ||||
Sequence: APPL → RPPA or FPPA | ||||||
Natural variant | VAR_080409 | 246-404 | in SCAR24; delocalizes protein to the nucleus; activates degradation through the ubiquitin proteasome pathway; decreases protein stability; disrupts interaction with UFM1 | |||
Sequence: Missing | ||||||
Mutagenesis | 250 | Abolished ability to activate UFM1. | ||||
Sequence: C → A | ||||||
Mutagenesis | 250 | Forms a stable intermediate complex. | ||||
Sequence: C → S | ||||||
Natural variant | VAR_077156 | 260 | in DEE44; reduces UFM1 activating enzyme activity; dbSNP:rs886039759 | |||
Sequence: V → M | ||||||
Mutagenesis | 271 | Impaired ability to activate UFM1 via a trans-binding mechanism. | ||||
Sequence: K → D | ||||||
Mutagenesis | 290 | Impaired homodimerization and ability to activate UFM1 via a trans-binding mechanism. | ||||
Sequence: D → K | ||||||
Natural variant | VAR_077157 | 310 | in SCAR24; does not affect cytoplasm localization; decreases protein stability; does not affect interaction with UFM1; dbSNP:rs886039762 | |||
Sequence: K → E | ||||||
Mutagenesis | 336 | Impaired ability to activate UFM1. | ||||
Sequence: H → A or D | ||||||
Mutagenesis | 341 | Abolished interaction with UFM1 and GABARAPL2. | ||||
Sequence: W → A | ||||||
Mutagenesis | 342 | Decreased interaction with UFM1 without affecting interaction with GABARAPL2. | ||||
Sequence: G → A | ||||||
Mutagenesis | 343 | Abolished interaction with UFM1 and decreased interaction with GABARAPL2. | ||||
Sequence: I → A | ||||||
Mutagenesis | 343-345 | Impaired ability to activate UFM1. | ||||
Sequence: IEL → AEA | ||||||
Mutagenesis | 345 | Abolished interaction with UFM1 and decreased interaction with GABARAPL2. | ||||
Sequence: L → A | ||||||
Mutagenesis | 346 | Abolished interaction with UFM1 and decreased interaction with GABARAPL2. | ||||
Sequence: V → A | ||||||
Natural variant | VAR_077158 | 371 | in DEE44; reduces UFM1 activating enzyme activity; reduces UFM1 activating enzyme activity; reduces UFM1-DDRGK1 formation; dbSNP:rs114925667 | |||
Sequence: A → T | ||||||
Mutagenesis | 372 | Strongly decreased ability to transfer UFM1 to UFC1. | ||||
Sequence: Y → A or E | ||||||
Mutagenesis | 372 | Does not affect ability to transfer UFM1 to UFC1. | ||||
Sequence: Y → F | ||||||
Natural variant | VAR_077159 | 389 | in DEE44; no effect on UFM1 activating enzyme activity; dbSNP:rs886039760 | |||
Sequence: D → Y | ||||||
Mutagenesis | 397 | Abolished interaction with UFC1. | ||||
Sequence: L → R | ||||||
Mutagenesis | 401 | Abolished interaction with UFC1. | ||||
Sequence: M → R |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 386 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue (large scale data), modified residue.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000194970 | 1-404 | UniProt | Ubiquitin-like modifier-activating enzyme 5 | |||
Sequence: MAESVERLQQRVQELERELAQERSLQVPRSGDGGGGRVRIEKMSSEVVDSNPYSRLMALKRMGIVSDYEKIRTFAVAIVGVGGVGSVTAEMLTRCGIGKLLLFDYDKVELANMNRLFFQPHQAGLSKVQAAEHTLRNINPDVLFEVHNYNITTVENFQHFMDRISNGGLEEGKPVDLVLSCVDNFEARMTINTACNELGQTWMESGVSENAVSGHIQLIIPGESACFACAPPLVVAANIDEKTLKREGVCAASLPTTMGVVAGILVQNVLKFLLNFGTVSFYLGYNAMQDFFPTMSMKPNPQCDDRNCRKQQEEYKKKVAALPKQEVIQEEEEIIHEDNEWGIELVSEVSEEELKNFSGPVPDLPEGITVAYTIPKKQEDSVTELTVEDSGESLEDLMAKMKNM | |||||||
Modified residue (large scale data) | 44 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 45 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 45 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 358 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 358 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 372 | PRIDE | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue (large scale data) | 381 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 393 | UniProt | Phosphoserine | ||||
Sequence: S |
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Widely expressed.
Gene expression databases
Organism-specific databases
Interaction
Subunit
Homodimer; homodimerization is required for UFM1 activation (PubMed:27653677, PubMed:29295865).
Interacts (via UIS motif) with UFM1; binds UFM1 via a trans-binding mechanism in which UFM1 interacts with distinct sites in both subunits of the UBA5 homodimer (PubMed:26872069, PubMed:26929408, PubMed:27653677, PubMed:28360427, PubMed:29295865, PubMed:30412706).
Interacts (via C-terminus) with UFC1 (PubMed:17825256, PubMed:27653677, PubMed:29868776, PubMed:34299007, PubMed:34588452).
Interacts (via UIS motif) with GABARAPL2 and, with lower affinity, with GABARAP and GABARAPL1 (PubMed:26929408, PubMed:30990354, PubMed:34299007).
Interacts (via UIS motif) with UFM1; binds UFM1 via a trans-binding mechanism in which UFM1 interacts with distinct sites in both subunits of the UBA5 homodimer (PubMed:26872069, PubMed:26929408, PubMed:27653677, PubMed:28360427, PubMed:29295865, PubMed:30412706).
Interacts (via C-terminus) with UFC1 (PubMed:17825256, PubMed:27653677, PubMed:29868776, PubMed:34299007, PubMed:34588452).
Interacts (via UIS motif) with GABARAPL2 and, with lower affinity, with GABARAP and GABARAPL1 (PubMed:26929408, PubMed:30990354, PubMed:34299007).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q9GZZ9 | GABARAP O95166 | 2 | EBI-747805, EBI-712001 | |
BINARY | Q9GZZ9 | GABARAPL1 Q9H0R8 | 2 | EBI-747805, EBI-746969 | |
BINARY | Q9GZZ9 | GABARAPL2 P60520 | 19 | EBI-747805, EBI-720116 | |
BINARY | Q9GZZ9 | MAP1LC3B Q9GZQ8 | 2 | EBI-747805, EBI-373144 | |
BINARY | Q9GZZ9 | MAP1LC3C Q9BXW4 | 2 | EBI-747805, EBI-2603996 | |
BINARY | Q9GZZ9 | UFM1 P61960 | 7 | EBI-747805, EBI-1045061 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for motif, region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Motif | 334-346 | UFM1-interacting sequence (UIS) | ||||
Sequence: IIHEDNEWGIELV | ||||||
Region | 347-377 | Linker | ||||
Sequence: SEVSEEELKNFSGPVPDLPEGITVAYTIPKK | ||||||
Motif | 389-404 | UFC1-binding sequence (UFC) | ||||
Sequence: DSGESLEDLMAKMKNM |
Domain
The UFC1-binding sequence (UFC) motif mediates interaction with UFC1.
The linker region is required to activate the active site of UFC1: it region moves next to active site of UFC1 to reduce the amount of water molecules in the vicinity of UFC1's active site and thereby elevate the nucleophilic activity of UFC1 active site.
The UFM1-interacting sequence (UIS) motif mediates interaction with both UFM1 and LC3/GABARAP proteins (GABARAP, GABARAPL1 and GABARAPL2).
Isoform 1
The N-terminus (1-56) contributes to the transfer of UFM1 from UBA5 to UFC1.
Sequence similarities
Belongs to the ubiquitin-activating E1 family. UBA5 subfamily.
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
Q9GZZ9-1
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
- SynonymsUBE1DC1A
- Length404
- Mass (Da)44,863
- Last updated2001-03-01 v1
- Checksum02F0F64FEAA1E880
Q9GZZ9-2
- Name2
- SynonymsUBE1DC1B
- Differences from canonical
- 1-56: Missing
Computationally mapped potential isoform sequences
There are 7 potential isoforms mapped to this entry
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_038528 | 1-56 | in isoform 2 | |||
Sequence: Missing | ||||||
Sequence conflict | 403 | in Ref. 4; BAB55199 | ||||
Sequence: N → S |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AB154406 EMBL· GenBank· DDBJ | BAD15375.1 EMBL· GenBank· DDBJ | mRNA | ||
AY253672 EMBL· GenBank· DDBJ | AAP79600.1 EMBL· GenBank· DDBJ | mRNA | ||
AL136757 EMBL· GenBank· DDBJ | CAB66691.1 EMBL· GenBank· DDBJ | mRNA | ||
AK026904 EMBL· GenBank· DDBJ | BAB15587.1 EMBL· GenBank· DDBJ | mRNA | ||
AK027563 EMBL· GenBank· DDBJ | BAB55199.1 EMBL· GenBank· DDBJ | mRNA | ||
AC020632 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471052 EMBL· GenBank· DDBJ | EAW79192.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471052 EMBL· GenBank· DDBJ | EAW79189.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471052 EMBL· GenBank· DDBJ | EAW79191.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC009737 EMBL· GenBank· DDBJ | AAH09737.1 EMBL· GenBank· DDBJ | mRNA |