UBA5 (ubiquitin-like modifier-activating enzyme 5) is the E1-activating enzyme of the ufmylation pathway, the first and rate-limiting step in conjugation of the ubiquitin-like modifier UFM1 to substrate proteins. UBA5 is a minimalistic, single-domain (ThiF/MoeB-type adenylation domain) E1 that functions as a homodimer. It activates mature UFM1 by adenylating UFM1's C-terminal glycine with ATP and then forming a high-energy thioester between that glycine and the catalytic cysteine (Cys250), releasing AMP. UFM1 is bound in trans across the two subunits of the UBA5 homodimer, and activated UFM1 is then transferred to the E2-conjugating enzyme UFC1 via UBA5's C-terminal UFC1-binding sequence. UBA5 binds zinc and uses a UFM1-interacting sequence (UIS) that also engages GABARAP/LC3 family proteins, which recruit UBA5 to the ER membrane. Acting at the cytosol and ER, UBA5-initiated ufmylation supports ribosome recycling, the response to ER stress, reticulophagy, the DNA-damage response, innate-immune (RIG-I/interferon) signaling, and erythroid/megakaryocyte differentiation. Biallelic UBA5 loss-of-function variants cause developmental and epileptic encephalopathy (DEE44) and autosomal-recessive spinocerebellar ataxia (SCAR24).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: UBA5 acts in the cytosol, where it activates UFM1. Supported by direct evidence (HPA IDA cytosol) and phylogenetic inference. Reason: Cytosol is the principal site where UBA5 activates UFM1; well supported. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0071569 protein ufmylation | IBA GO_REF:0000033 | ACCEPT | Summary: UBA5 is the E1 that initiates protein ufmylation; the process annotation is core and strongly supported across many studies. Reason: Ufmylation is the central process UBA5 enables; well supported by direct and phylogenetic evidence. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt E1-like enzyme which specifically catalyzes the first step in |
| GO:0071566 UFM1 activating enzyme activity | IBA GO_REF:0000033 | ACCEPT | Summary: UFM1 activating enzyme activity is UBA5's core molecular function: ATP-dependent adenylation and thioester formation with UFM1's C-terminal glycine. Strongly supported. Reason: This is the defining catalytic activity of UBA5 (the UFM1 E1); supported by direct biochemistry and phylogenetic inference. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt UFM1-activating enzyme |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UBA5 can localize to the nucleus (notably in the presence of SUMO2). Supported experimentally but a minor pool relative to its cytosolic site of action. Reason: Nuclear localization is documented but secondary; UBA5 mainly acts in the cytoplasm. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Nucleus |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic localization, consistent with the experimentally supported cytoplasm/cytosol annotations. Reason: Correct primary compartment for UBA5; agrees with direct evidence. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UBA5 localizes to the ER membrane through its GABARAPL2 interaction, consistent with ufmylation acting at ER-bound ribosomes. Reason: ER-membrane localization is directly supported (IDA, PMID:30990354) and functionally relevant to ER-associated ufmylation. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Golgi localization reported in one study (PMID:26872069). Minor and not clearly tied to UBA5's core ufmylation function. Reason: Documented but peripheral localization; not central to UBA5's UFM1-E1 function. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Golgi apparatus |
| GO:0008641 ubiquitin-like modifier activating enzyme activity | IEA GO_REF:0000002 | MODIFY | Summary: Family-level (InterPro) annotation of UBL-activating enzyme activity. This is correct but less precise than the specific UFM1-activating enzyme activity term. Reason: UBA5 is specific for UFM1; the general E1 term should be replaced by the precise UFM1 activating enzyme activity (GO:0071566). Proposed replacements: UFM1 activating enzyme activity Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt it is specific for UFM1 |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | KEEP AS NON CORE | Summary: High-throughput interaction (WITH GABARAPL2, P60520). The GABARAP/LC3 interactions recruit UBA5 to ER membranes; the generic term is uninformative. Reason: Records a real GABARAPL2 interaction (relevant to ER localization), but the generic protein binding term is uninformative and non-core. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Interacts (via UIS motif) with |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | KEEP AS NON CORE | Summary: Autophagy interaction network capturing UBA5 interactions with UFM1 (P61960) and GABARAP-family members. Generic protein binding term. Reason: Captures real cascade/recruitment interactions (UFM1, GABARAPs) but the generic MF term is uninformative. Supporting Evidence: file:human/UBA5/UBA5-goa.tsv UniProtKB:P61960 |
| GO:0005515 protein binding | IPI PMID:21900206 A directed protein interaction network for investigating int... | KEEP AS NON CORE | Summary: High-throughput interaction (WITH GABARAPL2, P60520). Generic protein binding term. Reason: Real GABARAPL2 interaction but the generic MF term is uninformative and non-core. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Interacts (via UIS motif) with |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Y2H interactome (WITH GABARAPL2, P60520). Generic protein binding term. Reason: Real GABARAPL2 interaction; generic MF term uninformative and non-core. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Interacts (via UIS motif) with |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | KEEP AS NON CORE | Summary: Quantitative interactome capturing UBA5-UFM1 (P61960). Generic protein binding term; the meaningful partner is the UFM1 substrate of activation. Reason: Real, mechanistically relevant UFM1 interaction, but the generic MF term is uninformative. Supporting Evidence: file:human/UBA5/UBA5-goa.tsv UniProtKB:P61960 |
| GO:0005515 protein binding | IPI PMID:26872069 UBA5 mutations cause a new form of autosomal recessive cereb... | KEEP AS NON CORE | Summary: SCAR24 disease study reporting UBA5-UFM1 (P61960) interaction. Generic term; UFM1 binding is the functionally meaningful interaction. Reason: Real UFM1 interaction underlying activation, but the generic MF term is uninformative. Supporting Evidence: file:human/UBA5/UBA5-goa.tsv UniProtKB:P61960 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: BioPlex interactome capturing UBA5 interactions with GABARAPL2 (P60520) and UFM1 (P61960). Generic protein binding term. Reason: Captures real cascade/recruitment interactions but the generic MF term is uninformative. Supporting Evidence: file:human/UBA5/UBA5-goa.tsv UniProtKB:P61960 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: HuRI binary interactome (WITH GABARAPL2, P60520). Generic protein binding term. Reason: Real GABARAPL2 interaction; generic MF term uninformative and non-core. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Interacts (via UIS motif) with |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex interactome capturing UBA5 interactions with GABARAPL2 (P60520) and UFM1 (P61960). Generic protein binding term. Reason: Captures real cascade/recruitment interactions but the generic MF term is uninformative. Supporting Evidence: file:human/UBA5/UBA5-goa.tsv UniProtKB:P61960 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | KEEP AS NON CORE | Summary: OpenCell interactome capturing UBA5-UFM1 (P61960). Generic protein binding term. Reason: Real UFM1 interaction; generic MF term uninformative and non-core. Supporting Evidence: file:human/UBA5/UBA5-goa.tsv UniProtKB:P61960 |
| GO:0005515 protein binding | IPI PMID:38225382 Systematic discovery of protein interaction interfaces using... | KEEP AS NON CORE | Summary: High-throughput interaction (WITH GABARAPL2, P60520). Generic protein binding term. Reason: Real GABARAPL2 interaction; generic MF term uninformative and non-core. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Interacts (via UIS motif) with |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Multimodal cell-maps interactome capturing UBA5 interactions with GABARAPL2 (P60520), UFM1 (P61960) and GABARAPL1 (Q9H0R8). Generic protein binding term. Reason: Captures real cascade/recruitment interactions but the generic MF term is uninformative. Supporting Evidence: file:human/UBA5/UBA5-goa.tsv UniProtKB:P61960 |
| GO:0030218 erythrocyte differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology-transferred role in erythroid differentiation, consistent with ufmylation being essential for erythroid/megakaryocyte differentiation in mouse. A downstream developmental consequence of ufmylation. Reason: Genuine ufmylation-dependent developmental process, but downstream of and non-core relative to UBA5's E1 activity. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt essential for erythroid differentiation of both megakaryocytes and |
| GO:0030219 megakaryocyte differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology-transferred role in megakaryocyte differentiation, consistent with the essential role of ufmylation in hematopoiesis. Downstream developmental consequence. Reason: Genuine ufmylation-dependent developmental process, but downstream of and non-core relative to UBA5's E1 activity. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt essential for erythroid differentiation of both megakaryocytes and |
| GO:0032649 regulation of type II interferon production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology-transferred role in interferon production, consistent with ufmylation regulating RIG-I/interferon innate-immune signaling. Downstream signaling consequence. Reason: Genuine ufmylation-associated innate-immune process, but downstream of and non-core relative to UBA5's E1 activity. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt interferon response |
| GO:0071566 UFM1 activating enzyme activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation of the core UFM1-activating enzyme activity, redundant with strong experimental support. Reason: Core molecular function; redundant with direct experimental evidence. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt UFM1-activating enzyme |
| GO:0071569 protein ufmylation | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation of the core ufmylation process, redundant with strong experimental support. Reason: Core biological process; redundant with direct experimental evidence. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt E1-like enzyme which specifically catalyzes the first step in |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) cytosolic localization, consistent with UBA5's principal site of action. Reason: IDA-supported cytosolic localization; correct compartment. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005634 nucleus | EXP PMID:18442052 UBE1DC1, an ubiquitin-activating enzyme, activates two diffe... | KEEP AS NON CORE | Summary: Experimental nuclear localization (induced in the presence of SUMO2). Documented but a minor pool. Reason: Supported nuclear localization but secondary to the cytoplasmic site of action. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt it localizes to the nucleus in presence of SUMO2 |
| GO:0005737 cytoplasm | EXP PMID:18442052 UBE1DC1, an ubiquitin-activating enzyme, activates two diffe... | ACCEPT | Summary: Experimental cytoplasmic localization, the principal compartment where UBA5 acts. Reason: Correct primary compartment; experimentally supported. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Localizes mainly in the |
| GO:0005794 Golgi apparatus | EXP PMID:26872069 UBA5 mutations cause a new form of autosomal recessive cereb... | KEEP AS NON CORE | Summary: Experimental Golgi localization from one study. Minor and not central to the ufmylation function. Reason: Documented but peripheral localization; non-core. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Golgi apparatus |
| GO:0071566 UFM1 activating enzyme activity | IDA PMID:34588452 Structural basis for UFM1 transfer from UBA5 to UFC1. | ACCEPT | Summary: Direct demonstration of UBA5's UFM1-activating enzyme activity in the context of UFM1 transfer from UBA5 to UFC1. Core MF. Reason: Core molecular function directly demonstrated. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt UFM1-activating enzyme |
| GO:0071569 protein ufmylation | IDA PMID:34588452 Structural basis for UFM1 transfer from UBA5 to UFC1. | ACCEPT | Summary: Direct evidence for UBA5's role in ufmylation (UFM1 transfer to UFC1). Core process. Reason: Core biological process; directly supported. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt E1-like enzyme which specifically catalyzes the first step in |
| GO:0071569 protein ufmylation | IMP PMID:30626644 Ribosomal protein RPL26 is the principal target of UFMylatio... | ACCEPT | Summary: Functional genetics (RPL26-UFMylation study) implicating UBA5 in ufmylation. Core process. Reason: Core process; supported by functional perturbation. Supporting Evidence: PMID:30626644 RPL26 is the principal target of UFM1 conjugation |
| GO:0005515 protein binding | IPI PMID:26929408 Structural and functional analysis of a novel interaction mo... | KEEP AS NON CORE | Summary: Structural/functional study of the UBA5 UIS motif, capturing interactions with UFM1 (P61960) and GABARAP-family proteins (GABARAP, GABARAPL1, GABARAPL2). Generic term; the interactions are mechanistically meaningful. Reason: Real UFM1/GABARAP interactions via the UIS motif, but the generic MF term is uninformative. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Interacts (via UIS motif) with |
| GO:0005515 protein binding | IPI PMID:30990354 An atypical LIR motif within UBA5 (ubiquitin like modifier a... | KEEP AS NON CORE | Summary: Study of the atypical LIR motif in UBA5 mediating GABARAPL2 (P60520) binding and ER-membrane localization. Generic term; interaction is functionally relevant. Reason: Real GABARAPL2 interaction underlying ER localization, but the generic MF term is uninformative. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt mediates membrane |
| GO:0071569 protein ufmylation | IDA PMID:26929408 Structural and functional analysis of a novel interaction mo... | ACCEPT | Summary: Direct evidence that the UBA5 UIS motif is required for ufmylation. Core process. Reason: Core process; directly supported. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt required for binding to ubiquitin-like |
| GO:0005515 protein binding | IPI PMID:34299007 A concerted action of UBA5 C-terminal unstructured regions i... | KEEP AS NON CORE | Summary: Study of UBA5 C-terminal regions in UFM1 transfer to UFC1, capturing UFM1 (P61960), UFC1 (Q9Y3C8) and GABARAP-family interactions. Generic term. Reason: Real, mechanistically central UFC1/UFM1 interactions, but the generic MF term is uninformative. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Interacts (via C-terminus) with UFC1 |
| GO:0005515 protein binding | IPI PMID:27653677 Trans-binding mechanism of ubiquitin-like protein activation... | KEEP AS NON CORE | Summary: Structure of the UBA5-UFM1 complex (WITH UFM1, P61960) revealing the trans-binding activation mechanism. Generic term; interaction is central. Reason: Mechanistically central UFM1 interaction, but the generic MF term is uninformative. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt binds UFM1 via a trans-binding mechanism |
| GO:0005515 protein binding | IPI PMID:29295865 Trans-binding of UFM1 to UBA5 stimulates UBA5 homodimerizati... | KEEP AS NON CORE | Summary: Study showing UFM1 trans-binding stimulates UBA5 homodimerization and ATP binding (WITH UFM1, P61960). Generic term; mechanistically meaningful. Reason: Real UFM1 interaction underlying activation; generic MF term uninformative. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt binds UFM1 via a trans-binding mechanism |
| GO:0005515 protein binding | IPI PMID:30412706 An N-terminal extension to UBA5 adenylation domain boosts UF... | KEEP AS NON CORE | Summary: Structural study of UBA5 N-terminal extension and UFM1 activation (WITH UFM1, P61960). Generic term; interaction is central. Reason: Real UFM1 interaction underlying activation; generic MF term uninformative. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt binds UFM1 via a trans-binding mechanism |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:30990354 An atypical LIR motif within UBA5 (ubiquitin like modifier a... | ACCEPT | Summary: Direct evidence that the GABARAPL2 interaction localizes UBA5 to the ER membrane, where ER-associated ufmylation occurs. Reason: IDA-supported ER-membrane localization, functionally relevant to ER-associated ufmylation. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt mediates membrane |
| GO:0008270 zinc ion binding | IDA PMID:27653677 Trans-binding mechanism of ubiquitin-like protein activation... | ACCEPT | Summary: UBA5 binds a structural zinc ion (coordinated by Cys/His residues), a conserved feature of its adenylation domain. Directly demonstrated. Reason: Zinc binding is a directly supported structural molecular function of UBA5's E1 domain. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Zn(2+) |
| GO:0008270 zinc ion binding | IDA PMID:30412706 An N-terminal extension to UBA5 adenylation domain boosts UF... | ACCEPT | Summary: Independent structural confirmation of zinc binding in UBA5's adenylation domain. Reason: Directly supported structural zinc binding. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Zn(2+) |
| GO:0030218 erythrocyte differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence/orthology-based erythroid differentiation role, redundant with the IEA annotation. Downstream developmental consequence of ufmylation. Reason: Genuine ufmylation-dependent developmental process; non-core relative to UBA5's E1 activity. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt essential for erythroid differentiation of both megakaryocytes and |
| GO:0030219 megakaryocyte differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence/orthology-based megakaryocyte differentiation role, redundant with the IEA annotation. Downstream developmental consequence. Reason: Genuine ufmylation-dependent developmental process; non-core relative to UBA5's E1 activity. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt essential for erythroid differentiation of both megakaryocytes and |
| GO:0034976 response to endoplasmic reticulum stress | IMP PMID:32160526 A genome-wide ER-phagy screen highlights key roles of mitoch... | KEEP AS NON CORE | Summary: Genome-wide ER-phagy screen implicating UBA5-initiated ufmylation in the ER-stress response. Downstream process of ufmylation. Reason: Genuine ufmylation-dependent process, but downstream of and non-core relative to UBA5's E1 activity. Supporting Evidence: PMID:32160526 ER-Resident UFMylation |
| GO:0042803 protein homodimerization activity | IDA PMID:27653677 Trans-binding mechanism of ubiquitin-like protein activation... | ACCEPT | Summary: UBA5 forms a homodimer, which is required for UFM1 activation via the trans-binding mechanism. Directly demonstrated and mechanistically core. Reason: Homodimerization is a directly supported molecular function essential for UBA5's UFM1-activating activity. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Homodimer; homodimerization is required for UFM1 activation |
| GO:0042803 protein homodimerization activity | IDA PMID:29295865 Trans-binding of UFM1 to UBA5 stimulates UBA5 homodimerizati... | ACCEPT | Summary: UFM1 trans-binding promotes UBA5 homodimerization; directly demonstrated. Reason: Directly supported homodimerization activity required for UFM1 activation. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Trans-binding also promotes stabilization of the |
| GO:0061709 reticulophagy | IMP PMID:32160526 A genome-wide ER-phagy screen highlights key roles of mitoch... | KEEP AS NON CORE | Summary: Genome-wide ER-phagy screen implicating UBA5-initiated ufmylation in reticulophagy. Downstream process. Reason: Genuine ufmylation-dependent process; non-core relative to UBA5's E1 activity. Supporting Evidence: PMID:32160526 ER-Resident UFMylation |
| GO:0071566 UFM1 activating enzyme activity | IDA PMID:27653677 Trans-binding mechanism of ubiquitin-like protein activation... | ACCEPT | Summary: Direct biochemical/structural demonstration of UFM1 activation (adenylation and thioester formation). Core MF. Reason: Core molecular function directly demonstrated. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt yielding a UFM1-E1 thioester and free AMP |
| GO:0071566 UFM1 activating enzyme activity | IDA PMID:29295865 Trans-binding of UFM1 to UBA5 stimulates UBA5 homodimerizati... | ACCEPT | Summary: Direct demonstration of UFM1 activation (enhanced ATP binding upon UFM1 trans-binding). Core MF. Reason: Core molecular function directly demonstrated. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt enhances ATP-binding |
| GO:0071566 UFM1 activating enzyme activity | IDA PMID:30412706 An N-terminal extension to UBA5 adenylation domain boosts UF... | ACCEPT | Summary: Direct demonstration that the UBA5 N-terminal extension boosts UFM1 activation. Core MF. Reason: Core molecular function directly demonstrated. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt UFM1-activating enzyme |
| GO:0071569 protein ufmylation | IDA PMID:27653677 Trans-binding mechanism of ubiquitin-like protein activation... | ACCEPT | Summary: Direct evidence for UBA5's role in ufmylation via UFM1 activation. Core process. Reason: Core process; directly supported. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt E1-like enzyme which specifically catalyzes the first step in |
| GO:0071569 protein ufmylation | IDA PMID:29295865 Trans-binding of UFM1 to UBA5 stimulates UBA5 homodimerizati... | ACCEPT | Summary: Direct evidence for UBA5's role in ufmylation. Core process. Reason: Core process; directly supported. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt E1-like enzyme which specifically catalyzes the first step in |
| GO:0071569 protein ufmylation | IDA PMID:30412706 An N-terminal extension to UBA5 adenylation domain boosts UF... | ACCEPT | Summary: Direct evidence for UBA5's role in ufmylation. Core process. Reason: Core process; directly supported. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt E1-like enzyme which specifically catalyzes the first step in |
| GO:0071569 protein ufmylation | IMP PMID:32160526 A genome-wide ER-phagy screen highlights key roles of mitoch... | ACCEPT | Summary: Functional perturbation in the ER-phagy screen implicating UBA5 in ufmylation. Core process. Reason: Core process; supported by functional perturbation. Supporting Evidence: PMID:32160526 ER-Resident UFMylation |
| GO:0005515 protein binding | IPI PMID:29868776 Biallelic UFM1 and UFC1 mutations expand the essential role ... | KEEP AS NON CORE | Summary: HLD14 study reporting UBA5 interaction with UFC1 (Q9Y3C8, the E2). Generic term; mechanistically central cascade interaction. Reason: Real UFC1 interaction underlying UFM1 transfer, but the generic MF term is uninformative. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt Interacts (via C-terminus) with UFC1 |
| GO:0050905 neuromuscular process | IGI PMID:26872069 UBA5 mutations cause a new form of autosomal recessive cereb... | KEEP AS NON CORE | Summary: Genetic-interaction-based annotation (with a Drosophila gene) of a neuromuscular process in the SCAR24 ataxia study. Indirect organismal phenotype. Reason: Reflects an organismal/neuromuscular phenotype of UBA5 dysfunction; downstream and non-core relative to its E1 activity. Supporting Evidence: file:human/UBA5/UBA5-goa.tsv neuromuscular process |
| GO:0005737 cytoplasm | IDA PMID:26872069 UBA5 mutations cause a new form of autosomal recessive cereb... | ACCEPT | Summary: Direct cytoplasmic localization, the principal compartment where UBA5 acts. Reason: Correct primary compartment; directly supported. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0071566 UFM1 activating enzyme activity | IMP PMID:27545681 Biallelic variants in UBA5 reveal that disruption of the UFM... | ACCEPT | Summary: DEE44 disease variants reduce/abolish UFM1 activating enzyme activity, directly implicating UBA5's catalytic function. Core MF. Reason: Core molecular function supported by disease-variant functional characterization. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt reduces UFM1 activating enzyme |
| GO:0071569 protein ufmylation | IMP PMID:27545681 Biallelic variants in UBA5 reveal that disruption of the UFM... | ACCEPT | Summary: DEE44 disease variants disrupt the UFM1 cascade, implicating UBA5 in ufmylation. Core process. Reason: Core process; supported by disease-variant functional characterization. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt E1-like enzyme which specifically catalyzes the first step in |
| GO:1990592 protein K69-linked ufmylation | IDA PMID:25219498 Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... | ACCEPT | Summary: UBA5 supports formation of K69-linked poly-UFM1 chains as the activating enzyme. A specific aspect of the core ufmylation process. Reason: Specific ufmylation chain-linkage process that UBA5 enables as the E1; supported. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt UFM1-activating enzyme |
| GO:0033146 regulation of intracellular estrogen receptor signaling pathway | IMP PMID:25219498 Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... | KEEP AS NON CORE | Summary: Ufmylation of ASC1 (substrate) regulates ERalpha signaling; UBA5 is required as the E1. Substrate-specific downstream signaling consequence. Reason: Substrate-specific downstream signaling outcome of ufmylation; non-core relative to UBA5's E1 activity. Supporting Evidence: file:human/UBA5/UBA5-goa.tsv regulation of intracellular estrogen receptor signaling pathway |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:23152784 Transcriptional regulation of the Ufm1 conjugation system in... | KEEP AS NON CORE | Summary: The UFM1 conjugation system (including UBA5) is induced by ER-stress and acts in the ER-stress response. Downstream process. Reason: Genuine ufmylation-associated process; downstream and non-core relative to UBA5's E1 activity. Supporting Evidence: file:human/UBA5/UBA5-goa.tsv response to endoplasmic reticulum stress |
| GO:0071569 protein ufmylation | IMP PMID:23152784 Transcriptional regulation of the Ufm1 conjugation system in... | ACCEPT | Summary: UBA5 acts upstream within the ufmylation process; the conjugation system is transcriptionally regulated by ER stress. Core process. Reason: Core process; UBA5 is the initiating E1. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt E1-like enzyme which specifically catalyzes the first step in |
| GO:0005737 cytoplasm | IDA GO_REF:0000054 | ACCEPT | Summary: Localization-database (LIFEdb) cytoplasmic localization, consistent with UBA5's principal compartment. Reason: Correct primary compartment; supported by direct localization data. Supporting Evidence: file:human/UBA5/UBA5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0071566 UFM1 activating enzyme activity | IDA PMID:15071506 A novel protein-conjugating system for Ufm1, a ubiquitin-fol... | ACCEPT | Summary: The founding study established UBA5 (Uba5) as the E1 that activates UFM1 by forming a high-energy thioester. Core MF. Reason: Core molecular function demonstrated in the defining ufmylation paper. Supporting Evidence: PMID:15071506 activated by a novel E1-like enzyme, Uba5, by forming a |
| GO:0071569 protein ufmylation | IDA PMID:15071506 A novel protein-conjugating system for Ufm1, a ubiquitin-fol... | ACCEPT | Summary: The founding study established UBA5 as the activating enzyme of the UFM1 conjugation system. Core process. Reason: Core process; demonstrated in the defining ufmylation paper. Supporting Evidence: PMID:15071506 activated by a novel E1-like enzyme, Uba5, by forming a |
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Download this section (compressed HTML)Q: How is UBA5 activity and UFM1 charging regulated in different subcellular/stress contexts (e.g. ER-membrane recruitment via GABARAP/LC3 versus cytosolic activity)?
Q: Why do specific DEE44 versus SCAR24 UBA5 variants produce distinct neurological phenotypes despite both impairing UFM1 activation?
Q: What is the functional significance of UBA5 phosphorylation (Ser45, Ser358) for its E1 activity or its interactions with UFM1/UFC1?
Experiment: Quantitative in vitro UFM1-charging assays (adenylation and thioester formation) comparing wild-type UBA5 with DEE44/SCAR24 disease variants to rank residual E1 activity against clinical severity.
Experiment: Structure-guided mutagenesis of the UIS and UFC motifs combined with cell-based ufmylation readouts (RPL26 UFMylation) to dissect UFM1 binding, GABARAP recruitment, and UFM1 handoff to UFC1.
Experiment: Proximity-labeling (BioID/TurboID) of UBA5 across resting and ER-stress conditions to map context-dependent localization and partners at the ER membrane.
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