Glutaredoxin-3 (GLRX3) is a cytosolic [2Fe-2S] iron-sulfur cluster chaperone that coordinates, transports, and delivers iron-sulfur clusters to target proteins in the cytosolic iron-sulfur cluster assembly (CIA) pathway. Despite having thioredoxin-like and glutaredoxin domains, GLRX3 lacks classical oxidoreductase activity. The protein contains an N-terminal thioredoxin-like domain (scaffolding function) and two C-terminal monothiol glutaredoxin domains with CGFS motifs that coordinate [2Fe-2S] clusters. GLRX3 forms homodimeric complexes bridged by [2Fe-2S] clusters, with glutathione serving as an essential cofactor. Key functions include transferring clusters to NUBP1 and other CIA machinery components, forming iron-responsive [2Fe-2S]-bridged complexes with BolA2, and regulating IRP1 iron-sulfur cluster maturation. Under oxidative stress, GLRX3 translocates to the nucleus where it participates in DNA damage response via ATR pathway and epigenetic regulation via PRC2/EED interaction. Essential for embryonic development - knockout is embryonic lethal.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosol - primary localization of GLRX3 under normal conditions. Reason: GLRX3 is predominantly cytosolic where it functions as an iron-sulfur cluster chaperone for the CIA pathway. Supporting Evidence: file:human/GLRX3/GLRX3-deep-research-perplexity.md Under normal growth conditions, GLRX3 is predominantly localized to the cytoplasm in a relatively diffuse distribution pattern file:human/GLRX3/GLRX3-deep-research-falcon.md See deep research file for comprehensive analysis |
| GO:0006879 intracellular iron ion homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: Intracellular iron ion homeostasis - core function of GLRX3. Reason: GLRX3 is critical for cellular iron homeostasis through regulation of IRP1 iron-sulfur cluster maturation and iron distribution. Supporting Evidence: file:human/GLRX3/GLRX3-deep-research-perplexity.md GLRX3 functions as a critical regulator of cellular iron homeostasis through multiple interconnected mechanisms that collectively ensure appropriate iron acquisition, utilization, and storage |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nucleus - GLRX3 translocates to nucleus under oxidative stress. Reason: GLRX3 undergoes stress-induced nuclear translocation where it participates in DNA damage response and epigenetic regulation. Supporting Evidence: file:human/GLRX3/GLRX3-deep-research-perplexity.md upon exposure to oxidative stress induced by hydrogen peroxide or other radical-generating agents, GLRX3 undergoes a reversible and redox-dependent translocation into the nucleus |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Cytosol - primary localization for GLRX3 function. Reason: GLRX3 is predominantly cytosolic where it functions in iron-sulfur cluster chaperoning. Supporting Evidence: file:human/GLRX3/GLRX3-deep-research-perplexity.md Under normal growth conditions, GLRX3 is predominantly localized to the cytoplasm |
| GO:0005938 cell cortex | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cell cortex localization - related to PKC-theta interaction at plasma membrane. Reason: GLRX3 translocates to plasma membrane/immunological synapse with PKC-theta upon T cell activation. Not a core localization but reflects specific signaling context. Supporting Evidence: file:human/GLRX3/GLRX3-deep-research-perplexity.md Upon activation of T cells through antigen receptor engagement, GLRX3 and PKCθ translocate together to the plasma membrane region extending into the immunological synapse |
| GO:0030018 Z disc | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Z disc localization - likely related to cardiac function. Reason: GLRX3/PICOT has documented roles in cardiac function. Z disc localization is tissue-specific in cardiac muscle, not core function. Supporting Evidence: file:human/GLRX3/GLRX3-deep-research-perplexity.md PICOT attenuates cardiac hypertrophy by disrupting calcineurin-NFAT signaling |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | MODIFY | Summary: Metal ion binding - GLRX3 coordinates iron within [2Fe-2S] clusters. Reason: More specifically, GLRX3 binds iron-sulfur clusters. The term GO:0051536 (iron-sulfur cluster binding) is more accurate. Proposed replacements: iron-sulfur cluster binding Supporting Evidence: file:human/GLRX3/GLRX3-deep-research-perplexity.md Human GLRX3 specifically functions as a [2Fe-2S] cluster chaperone, capable of binding two iron atoms coordinated with two sulfide atoms |
| GO:0051536 iron-sulfur cluster binding | IEA GO_REF:0000043 | ACCEPT | Summary: Iron-sulfur cluster binding - core molecular function of GLRX3. Reason: GLRX3 coordinates [2Fe-2S] clusters through its CGFS motifs for chaperoning to CIA pathway targets. Supporting Evidence: file:human/GLRX3/GLRX3-deep-research-perplexity.md Each Grx domain possesses a CGFS active site motif where the conserved cysteine residue serves as a critical ligand for iron-sulfur cluster coordination |
| GO:0005080 protein kinase C binding | IEA GO_REF:0000107 | ACCEPT | Summary: Protein kinase C binding - original discovery of GLRX3 as PKC-theta interactor. Reason: GLRX3 was originally discovered as PICOT (PKC-interacting cousin of thioredoxin) through its interaction with PKC-theta regulatory domain. Supporting Evidence: file:human/GLRX3/GLRX3-deep-research-perplexity.md The original discovery of GLRX3 identified its interaction with protein kinase C-theta (PKCθ), and subsequent studies have established that GLRX3 binds to the regulatory domain of PKCθ |
| GO:0030425 dendrite | IEA GO_REF:0000107 | UNDECIDED | Summary: Dendrite localization - inferred from ortholog but limited evidence. Reason: Limited direct evidence for GLRX3 localization to dendrites in humans. May be inferred from orthologs but not a core function. |
| GO:0005515 protein binding | IPI PMID:10636891 Inhibition of the c-Jun N-terminal kinase/AP-1 and NF-kappaB... | MODIFY | Summary: Original discovery paper showing GLRX3/PICOT interaction with PKC-theta. Reason: This study identified GLRX3 as PKC-theta interactor. More specific term GO:0005080 (protein kinase C binding) is appropriate. Proposed replacements: protein kinase C binding Supporting Evidence: PMID:10636891 We report the isolation and characterization of a cDNA encoding a novel 335-amino acid (37. 5-kDa) PKCtheta-interacting protein termed PICOT (for PKC-interacting cousin of thioredoxin). PICOT is expressed in various tissues, including in T cells, where it colocalizes with PKCtheta. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | REMOVE | Summary: High-throughput interactome mapping - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative and should be avoided. Large-scale interactome study without mechanistic insight. Supporting Evidence: PMID:16189514 Using a stringent, high-throughput yeast two-hybrid system, we tested pairwise interactions among the products of approximately 8,100 currently available Gateway-cloned open reading frames and detected approximately 2,800 interactions. |
| GO:0005515 protein binding | IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by... | REMOVE | Summary: Mass spectrometry-based interactome mapping - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative. High-throughput study without specific mechanistic context for GLRX3. Supporting Evidence: PMID:17353931 Here, we report the first large-scale study of protein-protein interactions in human cells using a mass spectrometry-based approach. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | REMOVE | Summary: Next-generation sequencing interactome study - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative. High-throughput methodology without mechanistic insight. Supporting Evidence: PMID:21516116 We describe a massively parallel interactome-mapping pipeline, Stitch-seq, that combines PCR stitching with next-generation sequencing and used it to generate a new human interactome dataset. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Proteome-scale interactome mapping - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative. High-throughput study without specific functional context. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: Study on interaction perturbations in genetic disorders - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative without identifying specific binding partner function. Supporting Evidence: PMID:25910212 Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. |
| GO:0005515 protein binding | IPI PMID:26302480 N-terminal domains mediate [2Fe-2S] cluster transfer from gl... | MODIFY | Summary: Study on iron-sulfur cluster transfer from GLRX3 to anamorsin - mechanistically relevant. Reason: This study describes specific GLRX3-anamorsin interaction for [2Fe-2S] cluster transfer. Should be annotated with iron-sulfur cluster transfer activity or iron-sulfur cluster assembly complex. Proposed replacements: iron-sulfur cluster assembly complex Supporting Evidence: PMID:26302480 We define a new role of human cytosolic monothiol glutaredoxin-3 (GRX3) in transferring its [2Fe-2S] clusters to human anamorsin, a physical and functional protein partner of GRX3 in the cytosol, whose [2Fe-2S] cluster-bound form is involved in the biogenesis of cytosolic and nuclear Fe-S proteins. |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | REMOVE | Summary: Alternative splicing and protein interactions - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative without specific functional context. Supporting Evidence: PMID:26871637 We have applied this strategy to the study of binary protein-protein interactions (PPIs) and identified widespread interaction differences due to alternative splicing ( Figure 1A ) |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | REMOVE | Summary: Barcode fusion genetics interactome screen - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative. High-throughput screening method without mechanistic insight. Supporting Evidence: PMID:27107012 Here, we report Barcode Fusion Genetics-Yeast Two-Hybrid (BFG-Y2H), by which a full matrix of protein pairs can be screened in a single multiplexed strain pool. |
| GO:0005515 protein binding | IPI PMID:27107014 An inter-species protein-protein interaction network across ... | REMOVE | Summary: Cross-species interactome study - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative. Comparative study without specific mechanistic context. Supporting Evidence: PMID:27107014 We systematically probed the yeast and human proteomes for interactions between proteins from these two species and functionally characterized the resulting inter-interactome network. |
| GO:0005515 protein binding | IPI PMID:27519415 A Glutaredoxin·BolA Complex Serves as an Iron-Sulfur Cluster... | MODIFY | Summary: Key study on GLRX3-BolA complex as iron-sulfur cluster chaperone - mechanistically relevant. Reason: This is a key mechanistic paper showing GLRX3-BolA2 [2Fe-2S]-bridged complex function. Should be annotated with iron-sulfur cluster assembly complex. Proposed replacements: iron-sulfur cluster assembly complex Supporting Evidence: PMID:27519415 We characterize cytosolic Glrx3·BolA2 as a [2Fe-2S] chaperone complex in human cells. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Interactome architecture study - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative. High-throughput study without specific functional context. Supporting Evidence: PMID:28514442 Here we present BioPlex 2.0 (Biophysical Interactions of ORFeome-derived complexes), which uses robust affinity purification-mass spectrometry methodology to elucidate protein interaction networks and co-complexes nucleated by more than 25% of protein-coding genes from the human genome |
| GO:0005515 protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | REMOVE | Summary: Interactome perturbation study for developmental disorders - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative without specific binding partner function. Supporting Evidence: PMID:29892012 Here we establish an experimentally and computationally integrated approach to investigate the functional impact of missense mutations in the context of the human interactome network |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Study on genetic variants disrupting protein interactions - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative without identifying specific binding partner function. Supporting Evidence: PMID:31515488 we leveraged the ExAC dataset of coding variants from 60,706 human exomes9 to systematically evaluate the impact of 2009 missense SNVs |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Reference binary protein interactome map - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative. Large-scale interactome study without mechanistic insight for GLRX3. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. With approximately 53,000 protein-protein interactions |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Dual proteome-scale interactome study - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative. High-throughput study without specific mechanistic context. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | ACCEPT | Summary: Self-association (homodimerization) from large-scale interactome study. Reason: GLRX3 forms homodimers bridged by [2Fe-2S] clusters. Self-association is functionally relevant for cluster coordination. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0042802 identical protein binding | IPI PMID:26302480 N-terminal domains mediate [2Fe-2S] cluster transfer from gl... | ACCEPT | Summary: Homodimerization for iron-sulfur cluster transfer function. Reason: GLRX3 homodimerization is essential for [2Fe-2S] cluster bridging and subsequent transfer to target proteins like anamorsin. Supporting Evidence: PMID:26302480 We define a new role of human cytosolic monothiol glutaredoxin-3 (GRX3) in transferring its [2Fe-2S] clusters to human anamorsin, a physical and functional protein partner of GRX3 in the cytosol |
| GO:0042802 identical protein binding | IPI PMID:27519415 A Glutaredoxin·BolA Complex Serves as an Iron-Sulfur Cluster... | ACCEPT | Summary: Homodimerization documented in key mechanistic study of GLRX3-BolA complex. Reason: GLRX3 homodimerization is critical for its iron-sulfur cluster chaperoning function. Supporting Evidence: PMID:27519415 We characterize cytosolic Glrx3·BolA2 as a [2Fe-2S] chaperone complex in human cells. |
| GO:0005634 nucleus | NAS PMID:32910989 Iron-sulfur cluster biogenesis, trafficking, and signaling: ... | ACCEPT | Summary: Nuclear localization from review on iron-sulfur cluster biogenesis and signaling. Reason: GLRX3 translocates to nucleus under oxidative stress for DNA damage response and epigenetic regulation. Supporting Evidence: PMID:32910989 The synthesis and trafficking of iron-sulfur (Fe-S) clusters in both prokaryotes and eukaryotes requires coordination within an expanding network of proteins that function in the cytosol, nucleus, mitochondria, and chloroplasts |
| GO:0005737 cytoplasm | NAS PMID:32910989 Iron-sulfur cluster biogenesis, trafficking, and signaling: ... | ACCEPT | Summary: Cytoplasm localization from review article. Reason: GLRX3 is predominantly cytoplasmic under normal conditions where it functions in iron-sulfur cluster chaperoning. Supporting Evidence: PMID:32910989 The synthesis and trafficking of iron-sulfur (Fe-S) clusters in both prokaryotes and eukaryotes requires coordination within an expanding network of proteins that function in the cytosol, nucleus, mitochondria, and chloroplasts |
| GO:0006879 intracellular iron ion homeostasis | IDA PMID:27519415 A Glutaredoxin·BolA Complex Serves as an Iron-Sulfur Cluster... | ACCEPT | Summary: Direct assay demonstrating GLRX3 role in intracellular iron homeostasis. Reason: PMID:27519415 demonstrated GLRX3 function in cellular iron homeostasis through IRP1 regulation and iron-sulfur cluster distribution. Supporting Evidence: PMID:27519415 We characterize cytosolic Glrx3·BolA2 as a [2Fe-2S] chaperone complex in human cells. |
| GO:0016226 iron-sulfur cluster assembly | IDA PMID:27519415 A Glutaredoxin·BolA Complex Serves as an Iron-Sulfur Cluster... | ACCEPT | Summary: Direct assay demonstrating GLRX3 role in iron-sulfur cluster assembly. Reason: Core function of GLRX3. It chaperones [2Fe-2S] clusters to CIA pathway components for cytosolic iron-sulfur protein maturation. Supporting Evidence: PMID:27519415 We characterize cytosolic Glrx3·BolA2 as a [2Fe-2S] chaperone complex in human cells. |
| GO:0045454 cell redox homeostasis | IDA PMID:27519415 A Glutaredoxin·BolA Complex Serves as an Iron-Sulfur Cluster... | KEEP AS NON CORE | Summary: Role in cell redox homeostasis through glutathione-dependent mechanisms. Reason: While GLRX3 has glutaredoxin domains, it lacks classical oxidoreductase activity. Redox homeostasis role may be indirect through iron-sulfur cluster-dependent processes rather than direct oxidoreductase function. Supporting Evidence: PMID:27519415 We characterize cytosolic Glrx3·BolA2 as a [2Fe-2S] chaperone complex in human cells. |
| GO:1990229 iron-sulfur cluster assembly complex | IPI PMID:22309771 Human glutaredoxin 3 forms [2Fe-2S]-bridged complexes with h... | ACCEPT | Summary: GLRX3 forms [2Fe-2S]-bridged complex with BolA2 protein. Reason: PMID:22309771 demonstrated that human GLRX3 forms [2Fe-2S]-bridged complexes with BolA2, functioning as part of CIA machinery. Supporting Evidence: PMID:22309771 Herein we provide biophysical and biochemical evidence that the two tandem Grx-like domains in human Glrx3 form similar [2Fe-2S]-bridged complexes with human BolA2. |
| GO:0044571 [2Fe-2S] cluster assembly | IDA PMID:27519415 A Glutaredoxin·BolA Complex Serves as an Iron-Sulfur Cluster... | ACCEPT | Summary: Direct role in [2Fe-2S] cluster assembly for CIA pathway. Reason: Core molecular function. GLRX3 coordinates and delivers [2Fe-2S] clusters to target proteins in the cytosolic iron-sulfur cluster assembly pathway. Supporting Evidence: PMID:27519415 We characterize cytosolic Glrx3·BolA2 as a [2Fe-2S] chaperone complex in human cells. |
| GO:0005515 protein binding | IPI PMID:15846844 Proteomic profiling of cellular proteins interacting with th... | REMOVE | Summary: Study on HCV core protein interactions - uninformative generic annotation. Reason: Per curation guidelines, generic "protein binding" is uninformative. Study focused on viral protein interactions without specific mechanistic insight for GLRX3 function. Supporting Evidence: PMID:15846844 To gain insights into cellular functions of the core protein by identification of cellular proteins interacting with the core protein, we employed a proteomic approach. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | UNDECIDED | Summary: RNA binding from mRNA-binding protein atlas study. Reason: High-throughput study identified GLRX3 as mRNA-binding protein. Unclear if this reflects true function or technical artifact. Not consistent with known iron-sulfur cluster chaperone function. Supporting Evidence: PMID:22658674 We identify 860 proteins that qualify as RBPs by biochemical and statistical criteria, adding more than 300 RBPs to those previously known |
| GO:0002026 regulation of the force of heart contraction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cardiac function regulation inferred from orthologs. Reason: GLRX3/PICOT has documented roles in cardiac function (attenuating hypertrophy). This represents tissue-specific function rather than core molecular activity. |
| GO:0002026 regulation of the force of heart contraction | ISS PMID:18258855 PICOT attenuates cardiac hypertrophy by disrupting calcineur... | KEEP AS NON CORE | Summary: Cardiac function from study on PICOT/calcineurin-NFAT signaling. Reason: PMID:18258855 demonstrated PICOT attenuates cardiac hypertrophy. Tissue-specific function rather than core molecular activity. Supporting Evidence: PMID:18258855 PICOT (protein kinase C-interacting cousin of thioredoxin) was previously shown to inhibit pressure overload-induced cardiac hypertrophy, concomitant with an increase in ventricular function and cardiomyocyte contractility. |
| GO:0010614 negative regulation of cardiac muscle hypertrophy | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of cardiac hypertrophy inferred from orthologs. Reason: Well-documented tissue-specific function of GLRX3/PICOT in cardiac muscle. Not core molecular function but represents important physiological role. |
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