UBA5

UniProt ID: Q9GZZ9
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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).

Existing Annotations Review

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

Core Functions

UBA5 is the E1-activating enzyme of the ufmylation cascade. As a homodimer it adenylates the C-terminal glycine of mature UFM1 with ATP and forms a high-energy thioester between that glycine and its catalytic Cys250 (releasing AMP), then transfers activated UFM1 to the E2 enzyme UFC1.

Molecular Function:
UFM1 activating enzyme activity
Cellular Locations:
cytosol endoplasmic reticulum membrane
Supporting Evidence:
  • file:human/UBA5/UBA5-uniprot.txt
    Activates UFM1 by first adenylating its C-terminal glycine residue with
  • file:human/UBA5/UBA5-uniprot.txt
    yielding a UFM1-E1 thioester and free AMP

UBA5 homodimerization is an integral part of its catalytic mechanism. The two subunits cooperate in a trans-binding mechanism in which UFM1 contacts distinct sites on both protomers, and dimerization is required for UFM1 activation.

Molecular Function:
protein homodimerization activity
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/UBA5/UBA5-uniprot.txt
    Homodimer; homodimerization is required for UFM1 activation

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000054
Gene Ontology annotation based on LIFEdb localization data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:15071506
A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier.
  • Established UBA5 (Uba5) as the E1-like enzyme that activates UFM1 by forming a high-energy thioester, and UFC1 as the cognate E2.
PMID:16189514
Towards a proteome-scale map of the human protein-protein interaction network.
PMID:18442052
UBE1DC1, an ubiquitin-activating enzyme, activates two different ubiquitin-like proteins.
  • Characterized UBA5 (UBE1DC1) subcellular localization (cytoplasm and, with SUMO2, nucleus) and its activating-enzyme activity; the SUMO2 claim was later superseded (UBA5 is specific for UFM1).
PMID:20562859
Network organization of the human autophagy system.
PMID:21900206
A directed protein interaction network for investigating intracellular signal transduction.
PMID:23152784
Transcriptional regulation of the Ufm1 conjugation system in response to disturbance of the endoplasmic reticulum homeostasis and inhibition of vesicle trafficking.
  • The UFM1 conjugation system (including UBA5) is induced by ER stress, linking ufmylation to ER homeostasis.
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivation and breast cancer development.
  • Ufmylation of ASC1 (requiring the UBA5 E1) regulates ERalpha signaling.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:26496610
A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
PMID:26872069
UBA5 mutations cause a new form of autosomal recessive cerebellar ataxia.
  • Biallelic UBA5 variants cause SCAR24; a truncating variant delocalizes UBA5 and disrupts its interaction with UFM1.
PMID:26929408
Structural and functional analysis of a novel interaction motif within UFM1-activating enzyme 5 (UBA5) required for binding to ubiquitin-like proteins and ufmylation.
  • Defined the UBA5 UIS motif that binds UFM1 and LC3/GABARAP proteins and is required for ufmylation.
PMID:27545681
Biallelic variants in UBA5 reveal that disruption of the UFM1 cascade can result in early-onset encephalopathy.
  • DEE44-causing UBA5 variants reduce or abolish UFM1 activating enzyme activity.
PMID:27653677
Trans-binding mechanism of ubiquitin-like protein activation revealed by a UBA5-UFM1 Complex.
  • Structural basis of UFM1 activation by UBA5 via a trans-binding mechanism across the homodimer; defines the catalytic Cys250 thioester and Zn site.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:29295865
Trans-binding of UFM1 to UBA5 stimulates UBA5 homodimerization and ATP binding.
  • UFM1 trans-binding stimulates UBA5 homodimerization and enhances ATP binding, promoting UFM1 activation.
PMID:29868776
Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development.
  • UBA5 interacts with UFC1 as part of the UFM1 transfer cascade.
PMID:30412706
An N-terminal extension to UBA5 adenylation domain boosts UFM1 activation: isoform-specific differences in ubiquitin-like protein activation.
  • The UBA5 N-terminal extension boosts UFM1 activation; structural characterization of the UBA5-UFM1 complex and zinc site.
PMID:30626644
Ribosomal protein RPL26 is the principal target of UFMylation.
  • RPL26 is the principal UFM1 target; the UBA5/UFC1/UFL1 machinery acts on ER-bound ribosomes.
PMID:30990354
An atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5.
  • An atypical LIR motif in UBA5 binds GABARAP-family proteins and recruits UBA5 to the ER membrane.
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitochondrial metabolism and ER-Resident UFMylation.
  • ER-resident UFMylation (initiated by UBA5) is required for reticulophagy and ER homeostasis.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34299007
A concerted action of UBA5 C-terminal unstructured regions is important for transfer of activated UFM1 to UFC1.
  • UBA5 C-terminal regions mediate transfer of activated UFM1 to the E2 UFC1.
PMID:34588452
Structural basis for UFM1 transfer from UBA5 to UFC1.
  • Defined the UBA5 UFC-binding sequence and the structural mechanism of UFM1 transfer from UBA5 to UFC1, including activation of the UFC1 active site.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:38225382
Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.

Suggested Questions for Experts

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?

Suggested Experiments

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.

πŸ“š Additional Documentation

Notes

(UBA5-notes.md)

UBA5 (Q9GZZ9) research notes

Summary

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).

Core functions (from review)

  • GO:0071566 UFM1 activating enzyme activity β€” UBA5 is the E1-activating enzyme of the ufmylation cascade. As a homodimer it adenylates the C-terminal glycine of mature UFM1 with ATP and forms a high-energy thioester between that glycine and its catalytic Cys250 (releasing AMP), then transfers activated UFM1 to the E2 enzyme UFC1.
  • GO:0042803 protein homodimerization activity β€” UBA5 homodimerization is an integral part of its catalytic mechanism. The two subunits cooperate in a trans-binding mechanism in which UFM1 contacts distinct sites on both protomers, and dimerization is required for UFM1 activation.

Provenance

Research and verbatim supporting quotes are recorded inline in UBA5-ai-review.yaml (per-annotation supported_by and references findings). This notes file summarizes the completed review; see the YAML for evidence citations.

Pn Notes

(UBA5-pn-notes.md)

UBA5 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9GZZ9
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07c
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • Description: 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).
  • Existing/core annotation action counts: ACCEPT: 33; KEEP_AS_NON_CORE: 33; MODIFY: 1

PN Consistency Summary

  • Consistency: Strong. Notes/review/PN agree UBA5 is the UFM1 E1 (adenylation + Cys250 thioester, homodimer). Review ACCEPTs GO:0071566 (UFM1 activating enzyme activity, IDA x5), GO:0071569, ER membrane and cytosol; MODIFY on GO:0008641β†’GO:0071566. Reticulophagy KEEP_AS_NON_CORE present in GOA. No contradictions.
  • PN story / NEW pressure: Everything the PN asserts (UFM1 activation, ufmylation, ERphagy) is already in GOA/review. GO:0006515 (verified) projected new_to_goa for the RQC group is broad; UBA5's RQC contribution is via ufmylation (GO:0071569) which is annotated. Conclusion: already captured; GO:0006515 over-reaches as a direct UBA5 annotation.
  • Evidence alignment: PN row 2 cites the ER-phagy screen (PMID:32160526, in GOA as IDA for reticulophagy); review uses UniProt + cascade PMIDs (15071506 etc.). Overlap on the ufmylation/ERphagy evidence; PN E1 row is domain-signature only (IPR000594).
  • Verdict: Consistent and complete; PN UFMylation/E1/ERphagy story fully captured. Specific GO:0071566 should be preferred over the PN's broad GO:0008641 at gene level; GO:0006515 not warranted as a direct add.

Full Consistency Review

  • UniProt: Q9GZZ9 Β· batch: proteostasis-batch-2026-06-07c Β· review status: complete (E1 core function + homodimerization; many protein-binding rows triaged)
  • PN placement: Translation|Cytosolic translation|Ribosome-associated QC|UFMylation; ALP|...|ERphagy|UFMylation of ER proteins; UPS|E1 activating enzymes|activation of UFM1 ; PN-node mapping: UFMylation typeβ†’GO:0071569; ERphagyβ†’GO:0061709; E1 groupβ†’GO:0008641 (broad UBL E1 activity); RQC groupβ†’GO:0006515.
  • Consistency: Strong. Notes/review/PN agree UBA5 is the UFM1 E1 (adenylation + Cys250 thioester, homodimer). Review ACCEPTs GO:0071566 (UFM1 activating enzyme activity, IDA x5), GO:0071569, ER membrane and cytosol; MODIFY on GO:0008641β†’GO:0071566. Reticulophagy KEEP_AS_NON_CORE present in GOA. No contradictions.
  • PN story / NEW pressure: Everything the PN asserts (UFM1 activation, ufmylation, ERphagy) is already in GOA/review. GO:0006515 (verified) projected new_to_goa for the RQC group is broad; UBA5's RQC contribution is via ufmylation (GO:0071569) which is annotated. Conclusion: already captured; GO:0006515 over-reaches as a direct UBA5 annotation.
  • Mapping strategy: Distinguish specific from broad MF β€” PN E1-group projects the broad GO:0008641 (ubiquitin-like modifier activating enzyme activity); the review correctly prefers the specific GO:0071566 (UFM1 activating enzyme activity) and even MODIFIES the IEA GO:0008641 toward it. PN should keep GO:0008641 as the safe group-level term but acknowledge the gene-level specific term is GO:0071566 (precedent: broader parents not propagated over specific). UBA5 does not change the node.
  • Evidence alignment: PN row 2 cites the ER-phagy screen (PMID:32160526, in GOA as IDA for reticulophagy); review uses UniProt + cascade PMIDs (15071506 etc.). Overlap on the ufmylation/ERphagy evidence; PN E1 row is domain-signature only (IPR000594).
  • Verdict: Consistent and complete; PN UFMylation/E1/ERphagy story fully captured. Specific GO:0071566 should be preferred over the PN's broad GO:0008641 at gene level; GO:0006515 not warranted as a direct add.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/UBA5/UBA5-ai-review.yaml
  • PN workbook rows: 3

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | UFMylation

  • UniProt: Q9GZZ9
  • In branches: TR, ALP, UPS
  • PN-node mapping records (path + ancestors):
    • [type] Translation|Cytosolic translation|Ribosome-associated QC|UFMylation
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0071569 protein ufmylation]
      rationale: This PN RQC type denotes UFM1 conjugation in ribosome quality control. Protein ufmylation is the shared process target.
    • [group] Translation|Cytosolic translation|Ribosome-associated QC
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006515 protein quality control for misfolded or incompletely synthesized proteins]
      rationale: The PN ribosome-associated quality-control group covers surveillance and disposal of stalled or defective nascent-chain translation products. GO lacks a dedicated ribosome-associated QC term in the local cache, so the broader protein-quality-control process is the best supported target.
    • [class] Translation|Cytosolic translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
      rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
    • [branch] Translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
      rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

PN row 2: Autophagy-Lysosome Pathway | Autophagy substrate selection | Marking substrates for selective autophagy | ERphagy | UFMylation of ER proteins

  • UniProt: Q9GZZ9
  • In branches: TR, ALP, UPS
  • Notes: E1-type protein that catalyzes UFMylation. Knockdown of UFL1 decreased DDRGK1 levels and inhibits ER-phagy.UFL1 UFMylates RPN1 and RPL26 to target ER sheets for degradation.
  • PN references (titles):
    • A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation - ScienceDirect
  • PN-node mapping records (path + ancestors):
    • [subtype] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy|UFMylation of ER proteins
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061709 reticulophagy]
      rationale: This PN subtype captures a specific ER-cargo marking mechanism used in ERphagy. Because GO uses reticulophagy for ER autophagy, this subtype can propagate to reticulophagy.
    • [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061709 reticulophagy]
      rationale: The PN ERphagy marking category captures factors that mark ER cargo for selective autophagic turnover. GO uses reticulophagy for this pathway, so propagation to reticulophagy is appropriate.
    • [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
    • [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 3: Ubiquitin Proteasome System | E1 activating enzymes | activation of UFM1

  • UniProt: Q9GZZ9
  • In branches: TR, ALP, UPS
  • Signature domains: IPR000594
  • Auxiliary domains: (none)
  • PN-node mapping records (path + ancestors):
    • [group] Ubiquitin Proteasome System|E1 activating enzymes|activation of UFM1
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0008641 ubiquitin-like modifier activating enzyme activity]
      rationale: This PN group represents E1 activation of the UFM1 modifier family. The generic GO activating enzyme activity term is the safest propagation target.
    • [class] Ubiquitin Proteasome System|E1 activating enzymes
      status=context_only scope=too_broad_to_propagate GO=[GO:0008641 ubiquitin-like modifier activating enzyme activity]
      rationale: This class is a real ubiquitin-like modifier E1 context, but it spans ubiquitin, SUMO, NEDD8, UFM1, URM1, ISG15, FAT10, and autophagy modifiers. Propagation is safer from the curated child groups.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (5)

  • GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Ribosome-associated QC
  • GO:0071569 protein ufmylation | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Translation|Cytosolic translation|Ribosome-associated QC|UFMylation
  • GO:0061709 reticulophagy | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy
  • GO:0061709 reticulophagy | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy|UFMylation of ER proteins
  • GO:0008641 ubiquitin-like modifier activating enzyme activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E1 activating enzymes|activation of UFM1

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

πŸ“„ View Raw YAML

 
id: Q9GZZ9
gene_symbol: UBA5
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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).
alternative_products:
- name: 1 (UBE1DC1A {ECO:0000303|PubMed:18442052})
  id: Q9GZZ9-1
- name: 2 (UBE1DC1B {ECO:0000303|PubMed:18442052})
  id: Q9GZZ9-2
  sequence_note: VSP_038528
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      UBA5 acts in the cytosol, where it activates UFM1. Supported by direct
      evidence (HPA IDA cytosol) and phylogenetic inference.
    action: ACCEPT
    reason: >-
      Cytosol is the principal site where UBA5 activates UFM1; well supported.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      UBA5 is the E1 that initiates protein ufmylation; the process annotation
      is core and strongly supported across many studies.
    action: ACCEPT
    reason: >-
      Ufmylation is the central process UBA5 enables; well supported by direct
      and phylogenetic evidence.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: E1-like enzyme which specifically catalyzes the first step in
- term:
    id: GO:0071566
    label: UFM1 activating enzyme activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      This is the defining catalytic activity of UBA5 (the UFM1 E1); supported
      by direct biochemistry and phylogenetic inference.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: UFM1-activating enzyme
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Nuclear localization is documented but secondary; UBA5 mainly acts in the
      cytoplasm.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Nucleus
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Cytoplasmic localization, consistent with the experimentally supported
      cytoplasm/cytosol annotations.
    action: ACCEPT
    reason: Correct primary compartment for UBA5; agrees with direct evidence.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UBA5 localizes to the ER membrane through its GABARAPL2 interaction,
      consistent with ufmylation acting at ER-bound ribosomes.
    action: ACCEPT
    reason: >-
      ER-membrane localization is directly supported (IDA, PMID:30990354) and
      functionally relevant to ER-associated ufmylation.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Golgi localization reported in one study (PMID:26872069). Minor and not
      clearly tied to UBA5's core ufmylation function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Documented but peripheral localization; not central to UBA5's UFM1-E1
      function.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Golgi apparatus
- term:
    id: GO:0008641
    label: ubiquitin-like modifier activating enzyme activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Family-level (InterPro) annotation of UBL-activating enzyme activity. This
      is correct but less precise than the specific UFM1-activating enzyme
      activity term.
    action: MODIFY
    reason: >-
      UBA5 is specific for UFM1; the general E1 term should be replaced by the
      precise UFM1 activating enzyme activity (GO:0071566).
    proposed_replacement_terms:
    - id: GO:0071566
      label: UFM1 activating enzyme activity
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: it is specific for UFM1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      High-throughput interaction (WITH GABARAPL2, P60520). The GABARAP/LC3
      interactions recruit UBA5 to ER membranes; the generic term is
      uninformative.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records a real GABARAPL2 interaction (relevant to ER localization), but the
      generic protein binding term is uninformative and non-core.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Interacts (via UIS motif) with
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20562859
  qualifier: enables
  review:
    summary: >-
      Autophagy interaction network capturing UBA5 interactions with UFM1
      (P61960) and GABARAP-family members. Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Captures real cascade/recruitment interactions (UFM1, GABARAPs) but the
      generic MF term is uninformative.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-goa.tsv
      supporting_text: UniProtKB:P61960
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21900206
  qualifier: enables
  review:
    summary: >-
      High-throughput interaction (WITH GABARAPL2, P60520). Generic protein
      binding term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real GABARAPL2 interaction but the generic MF term is uninformative and
      non-core.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Interacts (via UIS motif) with
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Y2H interactome (WITH GABARAPL2, P60520). Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Real GABARAPL2 interaction; generic MF term uninformative and non-core.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Interacts (via UIS motif) with
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: >-
      Quantitative interactome capturing UBA5-UFM1 (P61960). Generic protein
      binding term; the meaningful partner is the UFM1 substrate of activation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real, mechanistically relevant UFM1 interaction, but the generic MF term
      is uninformative.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-goa.tsv
      supporting_text: UniProtKB:P61960
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26872069
  qualifier: enables
  review:
    summary: >-
      SCAR24 disease study reporting UBA5-UFM1 (P61960) interaction. Generic
      term; UFM1 binding is the functionally meaningful interaction.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real UFM1 interaction underlying activation, but the generic MF term is
      uninformative.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-goa.tsv
      supporting_text: UniProtKB:P61960
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      BioPlex interactome capturing UBA5 interactions with GABARAPL2 (P60520)
      and UFM1 (P61960). Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Captures real cascade/recruitment interactions but the generic MF term is
      uninformative.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-goa.tsv
      supporting_text: UniProtKB:P61960
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      HuRI binary interactome (WITH GABARAPL2, P60520). Generic protein binding
      term.
    action: KEEP_AS_NON_CORE
    reason: Real GABARAPL2 interaction; generic MF term uninformative and non-core.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Interacts (via UIS motif) with
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      BioPlex interactome capturing UBA5 interactions with GABARAPL2 (P60520)
      and UFM1 (P61960). Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Captures real cascade/recruitment interactions but the generic MF term is
      uninformative.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-goa.tsv
      supporting_text: UniProtKB:P61960
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: >-
      OpenCell interactome capturing UBA5-UFM1 (P61960). Generic protein binding
      term.
    action: KEEP_AS_NON_CORE
    reason: Real UFM1 interaction; generic MF term uninformative and non-core.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-goa.tsv
      supporting_text: UniProtKB:P61960
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:38225382
  qualifier: enables
  review:
    summary: >-
      High-throughput interaction (WITH GABARAPL2, P60520). Generic protein
      binding term.
    action: KEEP_AS_NON_CORE
    reason: Real GABARAPL2 interaction; generic MF term uninformative and non-core.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Interacts (via UIS motif) with
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      Multimodal cell-maps interactome capturing UBA5 interactions with
      GABARAPL2 (P60520), UFM1 (P61960) and GABARAPL1 (Q9H0R8). Generic protein
      binding term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Captures real cascade/recruitment interactions but the generic MF term is
      uninformative.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-goa.tsv
      supporting_text: UniProtKB:P61960
- term:
    id: GO:0030218
    label: erythrocyte differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Orthology-transferred role in erythroid differentiation, consistent with
      ufmylation being essential for erythroid/megakaryocyte differentiation in
      mouse. A downstream developmental consequence of ufmylation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine ufmylation-dependent developmental process, but downstream of and
      non-core relative to UBA5's E1 activity.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: essential for erythroid differentiation of both megakaryocytes and
- term:
    id: GO:0030219
    label: megakaryocyte differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Orthology-transferred role in megakaryocyte differentiation, consistent
      with the essential role of ufmylation in hematopoiesis. Downstream
      developmental consequence.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine ufmylation-dependent developmental process, but downstream of and
      non-core relative to UBA5's E1 activity.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: essential for erythroid differentiation of both megakaryocytes and
- term:
    id: GO:0032649
    label: regulation of type II interferon production
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Orthology-transferred role in interferon production, consistent with
      ufmylation regulating RIG-I/interferon innate-immune signaling. Downstream
      signaling consequence.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine ufmylation-associated innate-immune process, but downstream of and
      non-core relative to UBA5's E1 activity.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: interferon response
- term:
    id: GO:0071566
    label: UFM1 activating enzyme activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated annotation of the core UFM1-activating enzyme activity,
      redundant with strong experimental support.
    action: ACCEPT
    reason: Core molecular function; redundant with direct experimental evidence.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: UFM1-activating enzyme
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Automated annotation of the core ufmylation process, redundant with strong
      experimental support.
    action: ACCEPT
    reason: Core biological process; redundant with direct experimental evidence.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: E1-like enzyme which specifically catalyzes the first step in
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct immunofluorescence (HPA) cytosolic localization, consistent with
      UBA5's principal site of action.
    action: ACCEPT
    reason: IDA-supported cytosolic localization; correct compartment.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:18442052
  qualifier: located_in
  review:
    summary: >-
      Experimental nuclear localization (induced in the presence of SUMO2).
      Documented but a minor pool.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported nuclear localization but secondary to the cytoplasmic site of
      action.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: it localizes to the nucleus in presence of SUMO2
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:18442052
  qualifier: located_in
  review:
    summary: >-
      Experimental cytoplasmic localization, the principal compartment where
      UBA5 acts.
    action: ACCEPT
    reason: Correct primary compartment; experimentally supported.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Localizes mainly in the
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: EXP
  original_reference_id: PMID:26872069
  qualifier: located_in
  review:
    summary: >-
      Experimental Golgi localization from one study. Minor and not central to
      the ufmylation function.
    action: KEEP_AS_NON_CORE
    reason: Documented but peripheral localization; non-core.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Golgi apparatus
- term:
    id: GO:0071566
    label: UFM1 activating enzyme activity
  evidence_type: IDA
  original_reference_id: PMID:34588452
  qualifier: enables
  review:
    summary: >-
      Direct demonstration of UBA5's UFM1-activating enzyme activity in the
      context of UFM1 transfer from UBA5 to UFC1. Core MF.
    action: ACCEPT
    reason: Core molecular function directly demonstrated.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: UFM1-activating enzyme
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:34588452
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence for UBA5's role in ufmylation (UFM1 transfer to UFC1).
      Core process.
    action: ACCEPT
    reason: Core biological process; directly supported.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: E1-like enzyme which specifically catalyzes the first step in
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:30626644
  qualifier: involved_in
  review:
    summary: >-
      Functional genetics (RPL26-UFMylation study) implicating UBA5 in
      ufmylation. Core process.
    action: ACCEPT
    reason: Core process; supported by functional perturbation.
    supported_by:
    - reference_id: PMID:30626644
      supporting_text: RPL26 is the principal target of UFM1 conjugation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26929408
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real UFM1/GABARAP interactions via the UIS motif, but the generic MF term
      is uninformative.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Interacts (via UIS motif) with
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30990354
  qualifier: enables
  review:
    summary: >-
      Study of the atypical LIR motif in UBA5 mediating GABARAPL2 (P60520)
      binding and ER-membrane localization. Generic term; interaction is
      functionally relevant.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real GABARAPL2 interaction underlying ER localization, but the generic MF
      term is uninformative.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: mediates membrane
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:26929408
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence that the UBA5 UIS motif is required for ufmylation. Core
      process.
    action: ACCEPT
    reason: Core process; directly supported.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: required for binding to ubiquitin-like
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34299007
  qualifier: enables
  review:
    summary: >-
      Study of UBA5 C-terminal regions in UFM1 transfer to UFC1, capturing UFM1
      (P61960), UFC1 (Q9Y3C8) and GABARAP-family interactions. Generic term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real, mechanistically central UFC1/UFM1 interactions, but the generic MF
      term is uninformative.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Interacts (via C-terminus) with UFC1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27653677
  qualifier: enables
  review:
    summary: >-
      Structure of the UBA5-UFM1 complex (WITH UFM1, P61960) revealing the
      trans-binding activation mechanism. Generic term; interaction is central.
    action: KEEP_AS_NON_CORE
    reason: >-
      Mechanistically central UFM1 interaction, but the generic MF term is
      uninformative.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: binds UFM1 via a trans-binding mechanism
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29295865
  qualifier: enables
  review:
    summary: >-
      Study showing UFM1 trans-binding stimulates UBA5 homodimerization and ATP
      binding (WITH UFM1, P61960). Generic term; mechanistically meaningful.
    action: KEEP_AS_NON_CORE
    reason: Real UFM1 interaction underlying activation; generic MF term uninformative.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: binds UFM1 via a trans-binding mechanism
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30412706
  qualifier: enables
  review:
    summary: >-
      Structural study of UBA5 N-terminal extension and UFM1 activation (WITH
      UFM1, P61960). Generic term; interaction is central.
    action: KEEP_AS_NON_CORE
    reason: Real UFM1 interaction underlying activation; generic MF term uninformative.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: binds UFM1 via a trans-binding mechanism
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:30990354
  qualifier: located_in
  review:
    summary: >-
      Direct evidence that the GABARAPL2 interaction localizes UBA5 to the ER
      membrane, where ER-associated ufmylation occurs.
    action: ACCEPT
    reason: >-
      IDA-supported ER-membrane localization, functionally relevant to
      ER-associated ufmylation.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: mediates membrane
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IDA
  original_reference_id: PMID:27653677
  qualifier: enables
  review:
    summary: >-
      UBA5 binds a structural zinc ion (coordinated by Cys/His residues), a
      conserved feature of its adenylation domain. Directly demonstrated.
    action: ACCEPT
    reason: >-
      Zinc binding is a directly supported structural molecular function of
      UBA5's E1 domain.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Zn(2+)
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IDA
  original_reference_id: PMID:30412706
  qualifier: enables
  review:
    summary: >-
      Independent structural confirmation of zinc binding in UBA5's adenylation
      domain.
    action: ACCEPT
    reason: Directly supported structural zinc binding.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Zn(2+)
- term:
    id: GO:0030218
    label: erythrocyte differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence/orthology-based erythroid differentiation role, redundant with the
      IEA annotation. Downstream developmental consequence of ufmylation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine ufmylation-dependent developmental process; non-core relative to
      UBA5's E1 activity.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: essential for erythroid differentiation of both megakaryocytes and
- term:
    id: GO:0030219
    label: megakaryocyte differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence/orthology-based megakaryocyte differentiation role, redundant with
      the IEA annotation. Downstream developmental consequence.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine ufmylation-dependent developmental process; non-core relative to
      UBA5's E1 activity.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: essential for erythroid differentiation of both megakaryocytes and
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IMP
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: >-
      Genome-wide ER-phagy screen implicating UBA5-initiated ufmylation in the
      ER-stress response. Downstream process of ufmylation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine ufmylation-dependent process, but downstream of and non-core
      relative to UBA5's E1 activity.
    supported_by:
    - reference_id: PMID:32160526
      supporting_text: ER-Resident UFMylation
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:27653677
  qualifier: enables
  review:
    summary: >-
      UBA5 forms a homodimer, which is required for UFM1 activation via the
      trans-binding mechanism. Directly demonstrated and mechanistically core.
    action: ACCEPT
    reason: >-
      Homodimerization is a directly supported molecular function essential for
      UBA5's UFM1-activating activity.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Homodimer; homodimerization is required for UFM1 activation
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:29295865
  qualifier: enables
  review:
    summary: >-
      UFM1 trans-binding promotes UBA5 homodimerization; directly demonstrated.
    action: ACCEPT
    reason: >-
      Directly supported homodimerization activity required for UFM1 activation.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Trans-binding also promotes stabilization of the
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IMP
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: >-
      Genome-wide ER-phagy screen implicating UBA5-initiated ufmylation in
      reticulophagy. Downstream process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine ufmylation-dependent process; non-core relative to UBA5's E1
      activity.
    supported_by:
    - reference_id: PMID:32160526
      supporting_text: ER-Resident UFMylation
- term:
    id: GO:0071566
    label: UFM1 activating enzyme activity
  evidence_type: IDA
  original_reference_id: PMID:27653677
  qualifier: enables
  review:
    summary: >-
      Direct biochemical/structural demonstration of UFM1 activation (adenylation
      and thioester formation). Core MF.
    action: ACCEPT
    reason: Core molecular function directly demonstrated.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: yielding a UFM1-E1 thioester and free AMP
- term:
    id: GO:0071566
    label: UFM1 activating enzyme activity
  evidence_type: IDA
  original_reference_id: PMID:29295865
  qualifier: enables
  review:
    summary: >-
      Direct demonstration of UFM1 activation (enhanced ATP binding upon UFM1
      trans-binding). Core MF.
    action: ACCEPT
    reason: Core molecular function directly demonstrated.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: enhances ATP-binding
- term:
    id: GO:0071566
    label: UFM1 activating enzyme activity
  evidence_type: IDA
  original_reference_id: PMID:30412706
  qualifier: enables
  review:
    summary: >-
      Direct demonstration that the UBA5 N-terminal extension boosts UFM1
      activation. Core MF.
    action: ACCEPT
    reason: Core molecular function directly demonstrated.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: UFM1-activating enzyme
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:27653677
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence for UBA5's role in ufmylation via UFM1 activation. Core
      process.
    action: ACCEPT
    reason: Core process; directly supported.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: E1-like enzyme which specifically catalyzes the first step in
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:29295865
  qualifier: involved_in
  review:
    summary: Direct evidence for UBA5's role in ufmylation. Core process.
    action: ACCEPT
    reason: Core process; directly supported.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: E1-like enzyme which specifically catalyzes the first step in
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:30412706
  qualifier: involved_in
  review:
    summary: Direct evidence for UBA5's role in ufmylation. Core process.
    action: ACCEPT
    reason: Core process; directly supported.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: E1-like enzyme which specifically catalyzes the first step in
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: >-
      Functional perturbation in the ER-phagy screen implicating UBA5 in
      ufmylation. Core process.
    action: ACCEPT
    reason: Core process; supported by functional perturbation.
    supported_by:
    - reference_id: PMID:32160526
      supporting_text: ER-Resident UFMylation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29868776
  qualifier: enables
  review:
    summary: >-
      HLD14 study reporting UBA5 interaction with UFC1 (Q9Y3C8, the E2). Generic
      term; mechanistically central cascade interaction.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real UFC1 interaction underlying UFM1 transfer, but the generic MF term is
      uninformative.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: Interacts (via C-terminus) with UFC1
- term:
    id: GO:0050905
    label: neuromuscular process
  evidence_type: IGI
  original_reference_id: PMID:26872069
  qualifier: involved_in
  review:
    summary: >-
      Genetic-interaction-based annotation (with a Drosophila gene) of a
      neuromuscular process in the SCAR24 ataxia study. Indirect organismal
      phenotype.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects an organismal/neuromuscular phenotype of UBA5 dysfunction;
      downstream and non-core relative to its E1 activity.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-goa.tsv
      supporting_text: neuromuscular process
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:26872069
  qualifier: located_in
  review:
    summary: >-
      Direct cytoplasmic localization, the principal compartment where UBA5
      acts.
    action: ACCEPT
    reason: Correct primary compartment; directly supported.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0071566
    label: UFM1 activating enzyme activity
  evidence_type: IMP
  original_reference_id: PMID:27545681
  qualifier: enables
  review:
    summary: >-
      DEE44 disease variants reduce/abolish UFM1 activating enzyme activity,
      directly implicating UBA5's catalytic function. Core MF.
    action: ACCEPT
    reason: >-
      Core molecular function supported by disease-variant functional
      characterization.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: reduces UFM1 activating enzyme
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:27545681
  qualifier: involved_in
  review:
    summary: >-
      DEE44 disease variants disrupt the UFM1 cascade, implicating UBA5 in
      ufmylation. Core process.
    action: ACCEPT
    reason: Core process; supported by disease-variant functional characterization.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: E1-like enzyme which specifically catalyzes the first step in
- term:
    id: GO:1990592
    label: protein K69-linked ufmylation
  evidence_type: IDA
  original_reference_id: PMID:25219498
  qualifier: involved_in
  review:
    summary: >-
      UBA5 supports formation of K69-linked poly-UFM1 chains as the activating
      enzyme. A specific aspect of the core ufmylation process.
    action: ACCEPT
    reason: >-
      Specific ufmylation chain-linkage process that UBA5 enables as the E1;
      supported.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: UFM1-activating enzyme
- term:
    id: GO:0033146
    label: regulation of intracellular estrogen receptor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:25219498
  qualifier: involved_in
  review:
    summary: >-
      Ufmylation of ASC1 (substrate) regulates ERalpha signaling; UBA5 is
      required as the E1. Substrate-specific downstream signaling consequence.
    action: KEEP_AS_NON_CORE
    reason: >-
      Substrate-specific downstream signaling outcome of ufmylation; non-core
      relative to UBA5's E1 activity.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-goa.tsv
      supporting_text: regulation of intracellular estrogen receptor signaling pathway
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IDA
  original_reference_id: PMID:23152784
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      The UFM1 conjugation system (including UBA5) is induced by ER-stress and
      acts in the ER-stress response. Downstream process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine ufmylation-associated process; downstream and non-core relative to
      UBA5's E1 activity.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-goa.tsv
      supporting_text: response to endoplasmic reticulum stress
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:23152784
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      UBA5 acts upstream within the ufmylation process; the conjugation system is
      transcriptionally regulated by ER stress. Core process.
    action: ACCEPT
    reason: Core process; UBA5 is the initiating E1.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: E1-like enzyme which specifically catalyzes the first step in
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: located_in
  review:
    summary: >-
      Localization-database (LIFEdb) cytoplasmic localization, consistent with
      UBA5's principal compartment.
    action: ACCEPT
    reason: Correct primary compartment; supported by direct localization data.
    supported_by:
    - reference_id: file:human/UBA5/UBA5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0071566
    label: UFM1 activating enzyme activity
  evidence_type: IDA
  original_reference_id: PMID:15071506
  qualifier: enables
  review:
    summary: >-
      The founding study established UBA5 (Uba5) as the E1 that activates UFM1 by
      forming a high-energy thioester. Core MF.
    action: ACCEPT
    reason: Core molecular function demonstrated in the defining ufmylation paper.
    supported_by:
    - reference_id: PMID:15071506
      supporting_text: activated by a novel E1-like enzyme, Uba5, by forming a
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:15071506
  qualifier: involved_in
  review:
    summary: >-
      The founding study established UBA5 as the activating enzyme of the UFM1
      conjugation system. Core process.
    action: ACCEPT
    reason: Core process; demonstrated in the defining ufmylation paper.
    supported_by:
    - reference_id: PMID:15071506
      supporting_text: activated by a novel E1-like enzyme, Uba5, by forming a
core_functions:
- description: >-
    UBA5 is the E1-activating enzyme of the ufmylation cascade. As a homodimer it
    adenylates the C-terminal glycine of mature UFM1 with ATP and forms a
    high-energy thioester between that glycine and its catalytic Cys250 (releasing
    AMP), then transfers activated UFM1 to the E2 enzyme UFC1.
  molecular_function:
    id: GO:0071566
    label: UFM1 activating enzyme activity
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/UBA5/UBA5-uniprot.txt
    supporting_text: Activates UFM1 by first adenylating its C-terminal glycine residue with
  - reference_id: file:human/UBA5/UBA5-uniprot.txt
    supporting_text: yielding a UFM1-E1 thioester and free AMP
- description: >-
    UBA5 homodimerization is an integral part of its catalytic mechanism. The two
    subunits cooperate in a trans-binding mechanism in which UFM1 contacts
    distinct sites on both protomers, and dimerization is required for UFM1
    activation.
  molecular_function:
    id: GO:0042803
    label: protein homodimerization activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/UBA5/UBA5-uniprot.txt
    supporting_text: Homodimer; homodimerization is required for UFM1 activation
proposed_new_terms: []
suggested_questions:
- question: >-
    How is UBA5 activity and UFM1 charging regulated in different
    subcellular/stress contexts (e.g. ER-membrane recruitment via GABARAP/LC3
    versus cytosolic activity)?
- question: >-
    Why do specific DEE44 versus SCAR24 UBA5 variants produce distinct
    neurological phenotypes despite both impairing UFM1 activation?
- question: >-
    What is the functional significance of UBA5 phosphorylation (Ser45, Ser358)
    for its E1 activity or its interactions with UFM1/UFC1?
suggested_experiments:
- description: >-
    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.
- description: >-
    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.
- description: >-
    Proximity-labeling (BioID/TurboID) of UBA5 across resting and ER-stress
    conditions to map context-dependent localization and partners at the ER
    membrane.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: >-
    Manual transfer of experimentally-verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000054
  title: Gene Ontology annotation based on LIFEdb localization data
  findings: []
- id: GO_REF:0000107
  title: >-
    Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15071506
  title: A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier.
  findings:
  - statement: >-
      Established UBA5 (Uba5) as the E1-like enzyme that activates UFM1 by forming
      a high-energy thioester, and UFC1 as the cognate E2.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Founding paper defining UBA5 as the UFM1 E1; PubMed-verified.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:18442052
  title: UBE1DC1, an ubiquitin-activating enzyme, activates two different ubiquitin-like proteins.
  findings:
  - statement: >-
      Characterized UBA5 (UBE1DC1) subcellular localization (cytoplasm and, with
      SUMO2, nucleus) and its activating-enzyme activity; the SUMO2 claim was
      later superseded (UBA5 is specific for UFM1).
    reference_section_type: RESULTS
- id: PMID:20562859
  title: Network organization of the human autophagy system.
  findings: []
- id: PMID:21900206
  title: A directed protein interaction network for investigating intracellular signal transduction.
  findings: []
- id: PMID:23152784
  title: >-
    Transcriptional regulation of the Ufm1 conjugation system in response to
    disturbance of the endoplasmic reticulum homeostasis and inhibition of
    vesicle trafficking.
  findings:
  - statement: >-
      The UFM1 conjugation system (including UBA5) is induced by ER stress,
      linking ufmylation to ER homeostasis.
    reference_section_type: ABSTRACT
- id: PMID:25219498
  title: >-
    Modification of ASC1 by UFM1 is crucial for ERΞ± transactivation and breast cancer development.
  findings:
  - statement: >-
      Ufmylation of ASC1 (requiring the UBA5 E1) regulates ERalpha signaling.
    reference_section_type: ABSTRACT
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:26496610
  title: >-
    A human interactome in three quantitative dimensions organized by
    stoichiometries and abundances.
  findings: []
- id: PMID:26872069
  title: UBA5 mutations cause a new form of autosomal recessive cerebellar ataxia.
  findings:
  - statement: >-
      Biallelic UBA5 variants cause SCAR24; a truncating variant delocalizes UBA5
      and disrupts its interaction with UFM1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: SCAR24 disease genetics; PubMed-verified.
- id: PMID:26929408
  title: >-
    Structural and functional analysis of a novel interaction motif within
    UFM1-activating enzyme 5 (UBA5) required for binding to ubiquitin-like
    proteins and ufmylation.
  findings:
  - statement: >-
      Defined the UBA5 UIS motif that binds UFM1 and LC3/GABARAP proteins and is
      required for ufmylation.
    reference_section_type: ABSTRACT
- id: PMID:27545681
  title: >-
    Biallelic variants in UBA5 reveal that disruption of the UFM1 cascade can
    result in early-onset encephalopathy.
  findings:
  - statement: >-
      DEE44-causing UBA5 variants reduce or abolish UFM1 activating enzyme
      activity.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: DEE44 disease genetics with functional E1-activity readouts.
- id: PMID:27653677
  title: >-
    Trans-binding mechanism of ubiquitin-like protein activation revealed by a
    UBA5-UFM1 Complex.
  findings:
  - statement: >-
      Structural basis of UFM1 activation by UBA5 via a trans-binding mechanism
      across the homodimer; defines the catalytic Cys250 thioester and Zn site.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Key mechanistic structure of the UBA5-UFM1 E1 reaction.
- id: PMID:28514442
  title: >-
    Architecture of the human interactome defines protein communities and
    disease networks.
  findings: []
- id: PMID:29295865
  title: >-
    Trans-binding of UFM1 to UBA5 stimulates UBA5 homodimerization and ATP
    binding.
  findings:
  - statement: >-
      UFM1 trans-binding stimulates UBA5 homodimerization and enhances ATP
      binding, promoting UFM1 activation.
    reference_section_type: ABSTRACT
- id: PMID:29868776
  title: >-
    Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in
    brain development.
  findings:
  - statement: UBA5 interacts with UFC1 as part of the UFM1 transfer cascade.
    reference_section_type: RESULTS
- id: PMID:30412706
  title: >-
    An N-terminal extension to UBA5 adenylation domain boosts UFM1 activation:
    isoform-specific differences in ubiquitin-like protein activation.
  findings:
  - statement: >-
      The UBA5 N-terminal extension boosts UFM1 activation; structural
      characterization of the UBA5-UFM1 complex and zinc site.
    reference_section_type: ABSTRACT
- id: PMID:30626644
  title: Ribosomal protein RPL26 is the principal target of UFMylation.
  findings:
  - statement: >-
      RPL26 is the principal UFM1 target; the UBA5/UFC1/UFL1 machinery acts on
      ER-bound ribosomes.
    reference_section_type: ABSTRACT
- id: PMID:30990354
  title: 'An atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5.'
  findings:
  - statement: >-
      An atypical LIR motif in UBA5 binds GABARAP-family proteins and recruits
      UBA5 to the ER membrane.
    reference_section_type: ABSTRACT
- id: PMID:32160526
  title: >-
    A genome-wide ER-phagy screen highlights key roles of mitochondrial
    metabolism and ER-Resident UFMylation.
  findings:
  - statement: >-
      ER-resident UFMylation (initiated by UBA5) is required for reticulophagy and
      ER homeostasis.
    reference_section_type: ABSTRACT
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33961781
  title: >-
    Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34299007
  title: >-
    A concerted action of UBA5 C-terminal unstructured regions is important for
    transfer of activated UFM1 to UFC1.
  findings:
  - statement: >-
      UBA5 C-terminal regions mediate transfer of activated UFM1 to the E2 UFC1.
    reference_section_type: ABSTRACT
- id: PMID:34588452
  title: Structural basis for UFM1 transfer from UBA5 to UFC1.
  findings:
  - statement: >-
      Defined the UBA5 UFC-binding sequence and the structural mechanism of UFM1
      transfer from UBA5 to UFC1, including activation of the UFC1 active site.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Mechanism of E1-to-E2 UFM1 handoff.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:38225382
  title: Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []