UBA5
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.
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).
Involvement in disease
Developmental and epileptic encephalopathy 44
DEE44
A 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.
None
The disease is caused by variants affecting the gene represented in this entry.
Spinocerebellar ataxia, autosomal recessive, 24
SCAR24
A 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.
None
The disease is caused by variants affecting the gene represented in this entry.
Sequence Similarities
Belongs to the ubiquitin-activating E1 family. UBA5 subfamily.
Tissue Specificity
Widely expressed.
Cellular localization
- Cytoplasm
- Nucleus
- Endoplasmic reticulum membrane
- Golgi apparatus
- Localizes mainly in the cytoplasm, while it localizes to the nucleus in presence of SUMO2 (PubMed:18442052). Interaction with GABARAPL2 promotes localization to the endoplasmic reticulum membrane (PubMed:30990354).
Alternative names
UBE1DC1, UBA5, Ubiquitin-like modifier-activating enzyme 5, Ubiquitin-activating enzyme 5, ThiFP1, UFM1-activating enzyme, Ubiquitin-activating enzyme E1 domain-containing protein 1