THG1L is the human tRNA(His) guanylyltransferase homolog (EC 2.7.7.79), a member of the Thg1 family that catalyzes an unusual 3'-5' nucleotidyl transfer: the post-transcriptional addition of a single guanylate (G-1) to the 5' end of tRNA(His), a residue required for tRNA(His) identity and correct aminoacylation. The enzyme is a homotetramer that uses a two-metal-ion (Mg2+) mechanism, binds GTP (the guanylyl donor) and ATP (used to activate the monophosphorylated tRNA 5' end), and shares active-site architecture with 5'-3' DNA polymerases and adenylyl/guanylyl cyclases despite lacking sequence similarity. Beyond its RNA-processing activity, THG1L (also called IHG-1, Induced in High Glucose-1) has a characterized moonlighting role at the mitochondrial outer membrane, where it binds the mitofusins MFN1 and MFN2 and acts as a guanine-nucleotide exchange factor, enhancing MFN2 GTP loading to promote mitochondrial fusion and to protect cells from oxidative-stress-induced apoptosis. The protein is found in both the cytosol and mitochondria. Biallelic loss-of-function variants cause an autosomal recessive spinocerebellar ataxia (SCAR28), and a disease variant (p.Val55Ala) impairs mitochondrial fusion.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0099116 tRNA 5'-end processing | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred biological process for the Thg1 family. The G-1 addition to the 5' end of tRNA(His) is precisely a 5'-end processing/maturation event, and this is the most specific and appropriate BP term for the core activity. Reason: Well-supported by the biochemically demonstrated 3'-5' guanylyl addition to the tRNA(His) 5' end; the IBA is at the correct level of specificity. |
| GO:0008193 tRNA guanylyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred core molecular function for the Thg1 family, consistent with the experimentally demonstrated activity of the human enzyme. Reason: This is the ancestral/core molecular function of THG1L, independently supported by IDA (PMID:21059936) and ISS from the yeast ortholog. |
| GO:0000287 magnesium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping for Mg2+ binding, confirmed experimentally: the human enzyme binds two catalytic magnesium ions per subunit as part of a two-metal-ion mechanism. Reason: Consistent with the crystal structure and cofactor requirement (PMID:21059936); duplicated by an IDA annotation below. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Subcellular-location mapping to cytoplasm. THG1L (originally described as the cytoplasmic protein ICF45) has a well-documented cytosolic pool. Reason: Consistent with UniProt subcellular location (Cytoplasm) and the more specific cytosol annotation below. |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Subcellular-location mapping to the mitochondrial outer membrane, where THG1L/IHG-1 engages the outer-membrane mitofusins MFN1/MFN2 to promote fusion. Reason: Consistent with the mitochondrial localization required for the MFN interaction (PMID:25008184). Supporting Evidence: PMID:25008184 IHG-1 must be localized to mitochondria to interact with Mfn1 and Mfn2, and this interaction is necessary for increased IHG-1-mediated mitochondrial fusion. |
| GO:0006400 tRNA modification | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping to the broad 'tRNA modification' process. The G-1 guanylylation is more precisely a 5'-end processing event (GO:0099116) than a nucleoside base modification, but the parent term is not incorrect for an electronic annotation. Reason: Acceptable as a broader IEA; the more precise BP (tRNA 5'-end processing) is captured by the IBA annotation. |
| GO:0008033 tRNA processing | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning annotation to the general 'tRNA processing' process, consistent with the enzyme's role in tRNA(His) maturation. Reason: Correct but general; more specific terms (tRNA 5'-end processing) are also annotated. A duplicate IDA annotation exists below. |
| GO:0008193 tRNA guanylyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (multi-method IEA) annotation of the core guanylyltransferase activity, based on InterPro/RHEA/EC:2.7.7.79 mappings. Reason: Duplicate of the experimentally supported core MF; correct. |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | KEEP AS NON CORE | Summary: IntAct interaction with the telomere factor TERF1/TRF1, captured in a genome-wide YFP complementation screen for telomere-signaling regulators. 'Protein binding' is uninformative and the interaction is not part of THG1L's characterized core function. Reason: Valid IPI record but uninformative (GO:0005515) and from a high-throughput screen with no established functional link to THG1L; retained as non-core. Supporting Evidence: PMID:21044950 Of the ∼12,000 human proteins examined, we identified over 300 proteins that associated with the six core telomeric proteins. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: IntAct interaction (with SDCBP) from the CCSB proteome-scale human interactome map (HuRI/ Rolland et al.). Uninformative 'protein binding' term from a systematic Y2H dataset. Reason: Valid but uninformative high-throughput interaction; not core. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: IntAct interactions (with LNX1, NTAQ1, PLEKHF2) from the HuRI binary reference interactome. Uninformative 'protein binding' term from a systematic screen with no established functional relationship to THG1L. Reason: Valid but uninformative high-throughput interactions; retained as non-core. |
| GO:0042802 identical protein binding | IPI PMID:21059936 tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleot... | KEEP AS NON CORE | Summary: Self-interaction (Q9NWX6-Q9NWX6). This is biologically meaningful because the active enzyme is a homotetramer, but 'identical protein binding' is a non-core molecular-function term; the oligomerization is better captured by protein homotetramerization (GO:0051289) below. Reason: Reflects the established homotetramer (PMID:21059936); kept as non-core detail of the quaternary structure. |
| GO:0042802 identical protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | KEEP AS NON CORE | Summary: Self-interaction detected by the Stitch-seq interactome pipeline, consistent with the homotetrameric assembly. Reason: Corroborates self-association; non-core. |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Self-interaction from the CCSB human interactome map, consistent with homotetramerization. Reason: Corroborates self-association; non-core. |
| GO:0016779 nucleotidyltransferase activity | EXP PMID:21059936 tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleot... | MODIFY | Summary: Reactome EXP annotation to the general parent 'nucleotidyltransferase activity'. The experimentally characterized activity is specifically tRNA(His) guanylyltransferase (3'-5' guanylyl addition), which is already annotated with IDA/IBA. Reason: Correct in essence but too general; the specific molecular function GO:0008193 (tRNA guanylyltransferase activity) is the accurate term and is already supported by IDA. Proposed replacements: tRNA guanylyltransferase activity Supporting Evidence: PMID:21059936 The tRNA His guanylyltransferase (Thg1) is a member of a unique enzyme family whose members catalyze an unprecedented reaction in biology: 3′-5′ addition of nucleotides to nucleic acid substrates. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial-proteome detection of THG1L in mitochondria, consistent with the characterized mitochondrial pool and the IHG-1 mitochondrial-fusion function. Reason: Corroborated by targeted evidence (PMID:25008184) and an independent IDA below. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. |
| GO:0006400 tRNA modification | TAS Reactome:R-HSA-6782434 | ACCEPT | Summary: Reactome TAS annotation ('THG1L transfers GMP to 5' end of tRNA(His)') mapped to the broad tRNA modification process. The event is more precisely tRNA 5'-end processing, but the annotation reflects the correct reaction. Reason: Author-stated (TAS) and mechanistically correct; the broader term is acceptable. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IDA PMID:25008184 IHG-1 increases mitochondrial fusion and bioenergetic functi... | ACCEPT | Summary: Direct experimental evidence that THG1L/IHG-1 acts as a GEF for the mitofusin MFN2 (and probably MFN1), enhancing its GTP-binding capacity. This is a well-characterized moonlighting molecular function distinct from the tRNA guanylyltransferase activity. Reason: Supported by IDA showing enhanced MFN2 GTP loading; a genuine second core function. Supporting Evidence: PMID:25008184 IHG-1 forms complexes with known mediators of mitochondrial fusion-mitofusins (Mfns) 1 and 2-and enhances the GTP-binding capacity of Mfn2, suggesting that IHG-1 acts as a guanine nucleotide exchange factor. |
| GO:1990046 stress-induced mitochondrial fusion | IDA PMID:25008184 IHG-1 increases mitochondrial fusion and bioenergetic functi... | ACCEPT | Summary: IHG-1 increases mitochondrial fusion and protects cells from ROS-induced apoptosis, linking its fusion-promoting activity to the oxidative-stress response. Reason: Directly supported; a specific and appropriate BP for the mitofusin-GEF moonlighting role. Supporting Evidence: PMID:25008184 overexpression of IHG-1 leads to increased mitochondrial fusion and also protects cells from reactive oxygen species-induced apoptosis. |
| GO:0006979 response to oxidative stress | IDA PMID:25008184 IHG-1 increases mitochondrial fusion and bioenergetic functi... | KEEP AS NON CORE | Summary: THG1L/IHG-1 promotes cell survival following oxidant stress via increased mitochondrial fusion and bioenergetic capacity. This is a broad downstream process rather than a core molecular activity. Reason: Experimentally supported but a general/downstream phenotype of the fusion function; retained as non-core. Supporting Evidence: PMID:25008184 these findings indicate that IHG-1 is a novel regulator of both mitochondrial dynamics and bioenergetic function and contributes to cell survival following oxidant stress. |
| GO:0005515 protein binding | IPI PMID:25008184 IHG-1 increases mitochondrial fusion and bioenergetic functi... | KEEP AS NON CORE | Summary: IntAct interactions with the mitofusins MFN1 (Q8IWA4) and MFN2 (O95140). These interactions are functionally important (they underlie the GEF/fusion role), but the generic 'protein binding' term is uninformative and the functional consequence is captured by the GEF-activity and mitochondrial-fusion annotations. Reason: Valid and functionally meaningful (MFN1/MFN2), but GO:0005515 is uninformative; the substance is annotated via GO:0005085 and GO:0008053. Supporting Evidence: PMID:25008184 IHG-1 forms complexes with known mediators of mitochondrial fusion-mitofusins (Mfns) 1 and 2 |
| GO:0008053 mitochondrial fusion | IDA PMID:25008184 IHG-1 increases mitochondrial fusion and bioenergetic functi... | ACCEPT | Summary: THG1L/IHG-1 is a direct regulator of mitochondrial fusion; loss of IHG-1 reduces fusion and overexpression increases it, through its mitofusin-GEF activity. Reason: Directly supported core biological process for the mitochondrial moonlighting function. Supporting Evidence: PMID:25008184 inhibition of endogenous IHG-1 expression results in reduced mitochondrial respiratory capacity, ATP production, and mitochondrial fusion. |
| GO:1990234 transferase complex | IDA PMID:21059936 tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleot... | KEEP AS NON CORE | Summary: The catalytically active enzyme is a homotetramer, i.e. a homo-oligomeric transferase complex. This captures the quaternary structure rather than a distinct hetero-complex. Reason: Correct (the homotetramer is a transferase complex) but non-core; the assembly is more informatively described by protein homotetramerization (GO:0051289). Supporting Evidence: PMID:21059936 The 2.3-Å crystal structure of human THG1 (hTHG1) reported here shows that, despite the lack of sequence similarity, hTHG1 shares unexpected structural homology with canonical 5′-3′ DNA polymerases |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6782434 | ACCEPT | Summary: Reactome author-stated cytosolic localization, where cytosolic tRNA(His) guanylylation would occur. Consistent with the original ICF45 cytoplasmic characterization. Reason: Appropriate specific location for the tRNA-processing activity. |
| GO:0000049 tRNA binding | TAS PMID:21059936 tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleot... | ACCEPT | Summary: THG1 binds its tRNA(His) substrate to catalyze 5' guanylyl addition; tRNA binding is an intrinsic feature of the enzyme. Reason: Supported by the enzyme's characterized activity on tRNA(His) substrates. Supporting Evidence: PMID:21059936 members catalyze an unprecedented reaction in biology: 3′-5′ addition of nucleotides to nucleic acid substrates. |
| GO:0000287 magnesium ion binding | IDA PMID:21059936 tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleot... | ACCEPT | Summary: Direct structural/biochemical evidence that the human enzyme binds two catalytic magnesium ions per subunit, used in a two-metal-ion catalytic mechanism. Reason: Supported by the crystal structure with magnesium and the proposed two-metal-ion mechanism. Supporting Evidence: PMID:21059936 hTHG1 shares unexpected structural homology with canonical 5′-3′ DNA polymerases and adenylyl/guanylyl cyclases, two enzyme families known to use a two-metal-ion mechanism for catalysis. |
| GO:0005524 ATP binding | IDA PMID:21059936 tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleot... | ACCEPT | Summary: ATP is required to activate the monophosphorylated tRNA(His) 5' end prior to guanylyl addition; ATP binding by the enzyme is directly supported. Reason: Consistent with the reaction mechanism, in which an additional ATP activates the 5' end. Supporting Evidence: PMID:21059936 The 3′-5′ addition reaction catalyzed by Thg1 requires consumption of an additional ATP to activate a monophosphorylated 5′-end for addition of the first nucleotide. |
| GO:0005525 GTP binding | IDA PMID:21059936 tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleot... | ACCEPT | Summary: GTP is the guanylyl donor for G-1 addition and was co-crystallized with the human enzyme; GTP binding is directly supported. Reason: Consistent with the co-crystal structure (GTP-bound) and the guanylyltransferase reaction. Supporting Evidence: PMID:21059936 members catalyze an unprecedented reaction in biology: 3′-5′ addition of nucleotides to nucleic acid substrates. |
| GO:0008033 tRNA processing | IDA PMID:21059936 tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleot... | ACCEPT | Summary: Direct evidence that the human enzyme processes tRNA(His) (5' guanylyl addition), placed under the general tRNA processing process. Reason: Correct though general; the more specific tRNA 5'-end processing is also annotated. Supporting Evidence: PMID:21059936 The tRNA His guanylyltransferase (Thg1) is a member of a unique enzyme family whose members catalyze an unprecedented reaction in biology: 3′-5′ addition of nucleotides to nucleic acid substrates. |
| GO:0008193 tRNA guanylyltransferase activity | IDA PMID:21059936 tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleot... | ACCEPT | Summary: Primary experimental evidence (structure + biochemistry of the human enzyme) for the core tRNA(His) guanylyltransferase activity: 3'-5' addition of GMP to the tRNA(His) 5' end. Reason: Best-supported statement of the core molecular function; anchors the primary core function. Supporting Evidence: PMID:21059936 The tRNA His guanylyltransferase (Thg1) is a member of a unique enzyme family whose members catalyze an unprecedented reaction in biology: 3′-5′ addition of nucleotides to nucleic acid substrates. |
| GO:0051289 protein homotetramerization | IPI PMID:21059936 tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleot... | ACCEPT | Summary: The active enzyme assembles into a homotetramer; mutagenesis (e.g. T127A) that abolishes oligomerization also abolishes activity, tying the quaternary structure to function. Reason: Directly supported by the structural and mutagenesis characterization of the human enzyme. Supporting Evidence: PMID:21059936 The 2.3-Å crystal structure of human THG1 (hTHG1) reported here |
| GO:0005739 mitochondrion | IDA GO_REF:0000054 | ACCEPT | Summary: Localization of an expressed fluorescent fusion protein to mitochondria (LIFEdb), consistent with the characterized mitochondrial pool of THG1L/IHG-1. Reason: Corroborated by targeted (PMID:25008184) and HTP mitochondrial-proteome evidence. |
| GO:0006400 tRNA modification | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer from the yeast ortholog (UniProtKB:P53215, Thg1) for the broad tRNA modification process. The core reaction (5' G-1 addition) is conserved. Reason: Reasonable ISS from a well-characterized ortholog; more precise terms are also annotated. |
| GO:0008193 tRNA guanylyltransferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of the guanylyltransferase activity from the yeast ortholog Thg1 (UniProtKB:P53215). Reason: Consistent with the experimentally demonstrated activity of the human enzyme; correct. |
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)