Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004791 thioredoxin-disulfide reductase (NADPH) activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA from PANTHER PTN005133404 (TrxR family; Trr2 is a donor via its own IDA). Correct. Supporting Evidence: file:yeast/TRR2/TRR2-uniprot.txt Reaction=[thioredoxin]-dithiol + NADP(+) = [thioredoxin]-disulfide + PMID:10037727 the recombinant Trx3 and Trr2 proteins were active in the insulin reduction assay
GO:0004791 thioredoxin-disulfide reductase (NADPH) activity	IDA PMID:10037727 Identification and functional characterization of a novel mi...	ACCEPT	Summary: Pedrajas et al. 1999: recombinant Trr2 (with Trx3) was active in the insulin reduction assay; CAVC active site and NADPH/FAD binding motifs. Core activity. Supporting Evidence: PMID:10037727 the recombinant Trx3 and Trr2 proteins were active in the insulin reduction assay PMID:10037727 The TRR2 gene codes for a protein of 37 kDa with the active-site motif (CAVC) present in prokaryotic thioredoxin reductases and binding sites for NADPH and FAD.
GO:0004791 thioredoxin-disulfide reductase (NADPH) activity	IEA GO_REF:0000120	ACCEPT	Summary: Combined IEA (ARBA, IPR005982, RHEA:20345, EC 1.8.1.9); correct. Supporting Evidence: file:yeast/TRR2/TRR2-uniprot.txt Reaction=[thioredoxin]-dithiol + NADP(+) = [thioredoxin]-disulfide +
GO:0004791 thioredoxin-disulfide reductase (NADPH) activity	RCA GO_REF:0000123	ACCEPT	Summary: YeastPathways thioredoxin pathway reaction (EC 1.8.1.9). The activity is correct, though the YeastCyc pathway is the cytosolic Trx1/Trx2 system; Trr2 acts on mitochondrial Trx3. Supporting Evidence: file:yeast/TRR2/TRR2-uniprot.txt FUNCTION: Acts on mitochondrial thioredoxin 3. Implicated in the
GO:0005515 protein binding	IPI PMID:16429126 Proteome survey reveals modularity of the yeast cell machine...	REMOVE	Summary: Bare protein binding is uninformative as an MF term; removal does not mean the interaction is false. High-throughput AP-MS (Gavin et al. 2006) with Trr1. Supporting Evidence: PMID:16429126 Proteome survey reveals modularity of the yeast cell machinery.
GO:0005515 protein binding	IPI PMID:18719252 High-quality binary protein interaction map of the yeast int...	REMOVE	Summary: Bare protein binding is uninformative as an MF term; removal does not mean the interaction is false. Yeast two-hybrid (Yu et al. 2008) with Trr1. Supporting Evidence: PMID:18719252 demonstrating that high-throughput yeast two-hybrid (Y2H) screening provides high-quality binary interaction information
GO:0005515 protein binding	IPI PMID:31454312 The role of structural pleiotropy and regulatory evolution i...	REMOVE	Summary: Bare protein binding is uninformative as an MF term; removal does not mean the interaction is false. Marchant et al. 2019 paralog heteromer study (Trr1-Trr2). Supporting Evidence: PMID:31454312 The role of structural pleiotropy and regulatory evolution in the retention of heteromers of paralogs.
GO:0005515 protein binding	IPI PMID:37968396 The social and structural architecture of the yeast protein ...	REMOVE	Summary: Bare protein binding is uninformative as an MF term; removal does not mean the interaction is false. Interactome study (Michaelis et al. 2023) with Trr1. Supporting Evidence: PMID:37968396 The social and structural architecture of the yeast protein interactome.
GO:0005737 cytoplasm	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO 'cytoplasm' from the TrxR family signature. Technically true (mitochondria are within the cytoplasm in GO) but misleading for the mitochondrial paralog, which has an N-terminal mitochondrial transit peptide. Reason: Replace with the experimentally supported mitochondrion. Proposed replacements: mitochondrion Supporting Evidence: PMID:10037727 By immunoblotting analysis of Saccharomyces subcellular fractions, we provide evidence that these proteins are located in mitochondria. file:yeast/TRR2/TRR2-uniprot.txt /note="Mitochondrion"
GO:0005739 mitochondrion	HDA PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimen...	ACCEPT	Summary: Mitochondrial proteome (Reinders et al. 2006); consistent with targeted evidence. Supporting Evidence: PMID:16823961 Toward the complete yeast mitochondrial proteome PMID:10037727 By immunoblotting analysis of Saccharomyces subcellular fractions, we provide evidence that these proteins are located in mitochondria.
GO:0005739 mitochondrion	HDA PMID:24769239 Quantitative variations of the mitochondrial proteome and ph...	ACCEPT	Summary: Mitochondrial proteome (Renvoise et al. 2014); consistent with targeted evidence. Supporting Evidence: PMID:24769239 Quantitative variations of the mitochondrial proteome and phosphoproteome during fermentative and respiratory growth in Saccharomyces cerevisiae. PMID:10037727 By immunoblotting analysis of Saccharomyces subcellular fractions, we provide evidence that these proteins are located in mitochondria.
GO:0005739 mitochondrion	IDA PMID:10037727 Identification and functional characterization of a novel mi...	ACCEPT	Summary: Pedrajas et al. 1999: immunoblotting of subcellular fractions places Trr2 in mitochondria. Supporting Evidence: PMID:10037727 By immunoblotting analysis of Saccharomyces subcellular fractions, we provide evidence that these proteins are located in mitochondria.
GO:0005739 mitochondrion	IEA GO_REF:0000044	ACCEPT	Summary: UniProt SubCell mapping; correct. Supporting Evidence: PMID:10037727 By immunoblotting analysis of Saccharomyces subcellular fractions, we provide evidence that these proteins are located in mitochondria.
GO:0005829 cytosol	IBA GO_REF:0000033	REMOVE	Summary: IBA (is_active_in cytosol) from PTN000530636, a node seeded by cytosolic Trr1 and C. albicans Trr1. Trr2 arose from the yeast whole-genome duplication and acquired a mitochondrial transit peptide; it is mitochondrial and acts on mitochondrial Trx3, so the cytosolic location is not inherited by this paralog. Reason: Target-specific divergence: Trr2 is mitochondrially targeted. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH WRONG ORTHOLOG OR PARALOG Sources checked: SGD:S000002761 · TRR1 SUPPORTS SOURCE BUT NOT TARGET Trr1 is cytosolic; its post-WGD paralog Trr2 gained a mitochondrial transit peptide. CGD:CAL0000184081 · C. albicans TRR1 SUPPORTS SOURCE BUT NOT TARGET Cytosolic ortholog of Trr1, not of the mitochondrial Trr2 paralog. Supporting Evidence: PMID:10037727 By immunoblotting analysis of Saccharomyces subcellular fractions, we provide evidence that these proteins are located in mitochondria. file:yeast/TRR2/TRR2-uniprot.txt /note="Mitochondrion"
GO:0005829 cytosol	RCA GO_REF:0000123	REMOVE	Summary: YeastPathways THIOREDOX-PWY assigns Trr2 to the cytosolic thioredoxin reaction. Trr2 is a mitochondrial enzyme reducing Trx3; the cytosolic compartment is wrong for this paralog. Reason: YeastCyc paralog conflation; Trr2 is mitochondrial. Supporting Evidence: PMID:10037727 By immunoblotting analysis of Saccharomyces subcellular fractions, we provide evidence that these proteins are located in mitochondria. file:yeast/TRR2/TRR2-uniprot.txt FUNCTION: Acts on mitochondrial thioredoxin 3. Implicated in the
GO:0016491 oxidoreductase activity	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO generic 'oxidoreductase activity'. Correct but uninformative. Reason: Replace with the specific TrxR term. Proposed replacements: thioredoxin-disulfide reductase (NADPH) activity Supporting Evidence: file:yeast/TRR2/TRR2-uniprot.txt Reaction=[thioredoxin]-dithiol + NADP(+) = [thioredoxin]-disulfide +
GO:0019430 removal of superoxide radicals	IEA GO_REF:0000002	REMOVE	Summary: InterPro2GO mapping from IPR005982 (thioredoxin reductase) to 'removal of superoxide radicals'. Thioredoxin reductase reduces thioredoxin with NADPH; it has no superoxide dismutase or superoxide-scavenging activity, and its antioxidant role is via thioredoxin-dependent peroxiredoxins acting on peroxides. The mapping is incorrect. Reason: Incorrect InterPro2GO mapping: TrxR does not remove superoxide. Supporting Evidence: file:yeast/TRR2/TRR2-uniprot.txt FUNCTION: Acts on mitochondrial thioredoxin 3. Implicated in the
GO:0034599 cellular response to oxidative stress	IMP PMID:10037727 Identification and functional characterization of a novel mi...	ACCEPT	Summary: Pedrajas et al. 1999: trr2 deletion mutants are more sensitive to H2O2. Supporting Evidence: PMID:10037727 The Deltatrr2 mutant was more sensitive to H2O2, whereas the Deltatrx3 mutant was as sensitive as the wild type.
GO:0045454 cell redox homeostasis	IBA GO_REF:0000033	ACCEPT	Summary: IBA from PTN005133404; maintaining reduced thioredoxin (Trx3) in mitochondria is the core process. Supporting Evidence: file:yeast/TRR2/TRR2-uniprot.txt FUNCTION: Acts on mitochondrial thioredoxin 3. Implicated in the

Core Functions

Mitochondrial NADPH-dependent thioredoxin reductase (EC 1.8.1.9) that reduces mitochondrial thioredoxin Trx3, sustaining the mitochondrial thioredoxin system (e.g. reduction of Prx1 and mitochondrial Gpx2) and protecting against H2O2.

Molecular Function:

thioredoxin-disulfide reductase (NADPH) activity

Directly Involved In:

cell redox homeostasis

Cellular Locations:

mitochondrion

Supporting Evidence:

PMID:10037727
the recombinant Trx3 and Trr2 proteins were active in the insulin reduction assay
PMID:10037727
By immunoblotting analysis of Saccharomyces subcellular fractions, we provide evidence that these proteins are located in mitochondria.
PMID:10037727
The Deltatrr2 mutant was more sensitive to H2O2, whereas the Deltatrx3 mutant was as sensitive as the wild type.

References

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Deep Research

SGD

(TRR2-deep-research-sgd.md)

SGD gene description for TRR2 (yeast) SGD

SGD gene description for TRR2 (yeast)

Mitochondrial thioredoxin reductase; involved in protection against oxidative stress, required with Glr1p to maintain the redox state of Trx3p; contains active-site motif (CAVC) present in prokaryotic orthologs; binds NADPH and FAD; TRR2 has a paralog, TRR1, that arose from the whole genome duplication

📚 Additional Documentation

Notes

(TRR2-notes.md)

TRR2 (YHR106W, P38816) notes

Module context: glutathione_thioredoxin_redox_systems; YeastCyc places it on the (cytosolic) thioredoxin pathway reaction, EC 1.8.1.9.

Mitochondrial TrxR acting with Trx3 [PMID:10037727 "the recombinant Trx3 and Trr2 proteins were active in the insulin reduction assay"; "we provide evidence that these proteins are located in mitochondria"]
trr2 deletion is H2O2-sensitive PMID:10037727
Transit peptide 1..23 [UniProt:P38816]

Conclusions

MF correct. Cytosol IBA (node seeded by cytosolic Trr1) and YeastCyc cytosol RCA removed: paralog/compartment conflation. Generic cytoplasm IEA modified to mitochondrion.

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