C28G1.2

UniProt ID: Q18287
Organism: Caenorhabditis elegans
Review Status: COMPLETE
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Gene Description

C28G1.2 (WBGene00016187, X chromosome) encodes a 265-residue member of the serpin superfamily, the only protein product annotated for the gene. In the PANTHER serpin tree it is one of the paralogous lineages that arose by duplication within the Caenorhabditis intracellular (clade L) serpins, next to the inhibitory serpins SRP-1, SRP-2, SRP-3 and SRP-6/7/8, and it has an ortholog only in other Caenorhabditis species. Compared with those paralogs it is markedly shorter and more divergent: it retains a compact serpin-fold-like scaffold but lacks the hinge and reactive-centre loop that inhibitory serpins use to trap target proteases, as well as several segments of the N-terminal half. It has no predicted signal peptide or transmembrane segment, like its cytosolic paralogs. Its molecular function, localization and biological role have not been studied and remain unknown; the loss of the reactive-centre loop suggests it is not a serpin-mechanism protease inhibitor.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005576 extracellular region
IBA
GO_REF:0000033 		REMOVE
Summary: Root-level PAINT localization (PTN000156123, Archaea-Eukaryota) propagated into the nematode intracellular serpin clade, where the experimental evidence points the other way. The local PANTHER tree places C28G1.2 inside the Caenorhabditis duplication node PTN002479232 together with SRP-1, SRP-2, SRP-3 and SRP-6/7/8. The nematode serpins lack signal peptides, and their GFP fusions are cytoplasmic with no evidence of secretion. SRP-2 in particular is demonstrably cytosolic and is retained in the ER rather than secreted even when given an artificial signal peptide. C28G1.2 itself has no predicted signal peptide or transmembrane segment (Phobius). None of the seeds of the root node is a nematode protein. PAINT already records the analogous exception for the vertebrate intracellular clade B serpins (NOT extracellular region at PTN002606963) but has no equivalent negation at the nematode node. On biological grounds the extracellular localization is not expected to hold for this lineage. No positive localization can be substituted, because C28G1.2 has not been localized experimentally.
Reason: An over-propagated IBA that biological evidence argues against. The nearest relatives of C28G1.2 in the tree (the paralogous C. elegans intracellular serpins) are cytosolic and lack signal peptides, and the target has no secretion signal either. The ancestral extracellular state at the family root was evidently replaced in the nematode clade, as it was in vertebrate clade B, where PAINT curators negated it explicitly.
Propagation Review
Root cause: PROPAGATION BAD
Failure modes: COMPARTMENT OR COMPLEX MISMATCH LINEAGE OR TAXON MISMATCH
Sources checked:
PANTHER:PTN000156123 · PTHR11461 family root (Archaea-Eukaryota) SUPPORTS SOURCE BUT NOT TARGET
The extracellular state is well supported by the secreted serpins among the seeds, none of which is a nematode protein. Within the root, C28G1.2 descends through the nematode intracellular serpin clade (PTN002479231 -> PTN002479232), whose characterised members are cytosolic and lack signal peptides. PAINT has no NOT at this clade, although it has one for vertebrate clade B (PTN002606963).
Supporting Evidence:
PMID:25786854
Similar to the clade B serpins, these nematode serpins lacked a signal peptide and the N- and C-terminal extensions typical of serpins transiting the conventional ER–Golgi secretory pathway.
PMID:25786854
Green fluorescent protein (GFP)–nematode serpin fusions show a diffuse cytoplasmic appearance and no evidence of secretion into the intestinal cell lumen, the pseudocoelomic space, or the cuticle
PMID:14739286
they lack typical N-terminal signal peptides and reside intracellularly
file:worm/C28G1.2/C28G1.2-bioinformatics/RESULTS.md
Phobius predicts no signal peptide and no transmembrane segment.
file:worm/C28G1.2/C28G1.2-bioinformatics/RESULTS.md
PTN002479232 is a multifurcating duplication node whose children are the C. elegans/C. briggsae paralog lineages

References

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Suggested Questions for Experts

Q: PAINT node PTN002479231 (Rhabditida-Chromadorea) now carries an IBD for GO:0004867 serine-type endopeptidase inhibitor activity, and C28G1.2 descends from it. Should the C28G1.2 lineage (PTN007508270) carry an IKR/NOT for that activity, given that it lacks the hinge and reactive-centre loop? And should the nematode intracellular serpin clade carry a NOT for GO:0005576 extracellular region, as the vertebrate clade B node PTN002606963 already does?

Q: Does purified C28G1.2 adopt a serpin fold, and does it bind any protease or other partner despite lacking a reactive-centre loop?

Q: Is C28G1.2 expressed, and in which tissues and subcellular compartment?

Suggested Experiments

Experiment: Endogenous CRISPR tagging of C28G1.2 (e.g. C-terminal GFP or epitope) to determine its expression pattern and subcellular localization, comparing it with cytosolic SRP-2 and SRP-6.

Hypothesis: Like its paralogs, C28G1.2 is a cytosolic protein that is not secreted.

Experiment: Express recombinant C28G1.2 and test it against the proteases targeted by its paralogs (granzyme B, cathepsins L/K/S/V, calpain, chymotrypsin). Measure SDS-stable complex formation and the stoichiometry of inhibition, and use SRP-2 as a positive control.

Hypothesis: Because it lacks a reactive-centre loop, C28G1.2 does not inhibit proteases by the serpin mechanism.

External Prediction Reviews

These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.

ProtNLM2 External predictions

View prediction review YAML · C28G1.2-protnlm-predictions-review.yaml · Review status: COMPLETE

C28G1.2 is a compact, divergent member of the Caenorhabditis intracellular serpin clade. It retains a serpin-fold-like scaffold but has no counterpart to the hinge and reactive-centre loop that its inhibitory paralogs (SRP-1, -2, -3, -6) use to trap proteases, and its function has not been studied experimentally (no PubMed record names the gene). Both ProtNLM2 GO claims assert serine protease inhibition, which the serpin suicide-substrate mechanism cannot deliver without a reactive-centre loop; both are scored as transfers of an inhibitory function onto a lineage that has lost the required structural element. This rests on sequence analysis, not on a biochemical assay.

Source documents: genes/worm/C28G1.2/C28G1.2-protnlm-source.json · genes/worm/C28G1.2/C28G1.2-notes.md · genes/worm/C28G1.2/C28G1.2-ai-review.yaml

Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.

GO:0010466 negative regulation of peptidase activity GO_BP
NPI — Nonparalog incorrect Review score: 0/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-10 · file:worm/C28G1.2/C28G1.2-protnlm-source.json
PSEUDOENZYME OVERANNOTATION
Review rationale: The process claim depends on C28G1.2 acting as a serpin-type protease inhibitor. Local alignment to its inhibitory paralogs shows no counterpart to the hinge and reactive-centre loop, the element serpins use to trap target proteases, so the inhibitory function of the clade is not expected to hold for this divergent lineage. C. elegans serpins with demonstrated inhibitory activity are restricted to five full-length members, which do not include C28G1.2. No other mechanism of peptidase regulation has been reported for the gene; the conclusion is a sequence-level inference that no biochemical assay has tested.
Supporting Evidence:
  • file:worm/C28G1.2/C28G1.2-bioinformatics/RESULTS.md: "In every local alignment, the paralog's hinge/reactive-centre-loop segment has no counterpart in Q18287"
  • PMID:25786854: "However, only SRP-1 , SRP-2 , SRP-3 , SRP-6 , and SRP-7 are synthesized as full-length proteins and serve as bona fide proteinase inhibitors, with the rest being transcribed pseudogenes or noninhibitory variants"
GO:0004867 serine-type endopeptidase inhibitor activity GO_MF
NPI — Nonparalog incorrect Review score: 0/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-10 · file:worm/C28G1.2/C28G1.2-protnlm-source.json
PSEUDOENZYME OVERANNOTATION
Review rationale: Serine-protease inhibition by serpins requires an exposed reactive-centre loop that the target protease cleaves and is then trapped by. C28G1.2 retains a compact serpin-fold-like scaffold, but alignment to SRP-1, SRP-2, SRP-3 and SRP-6 shows no counterpart to their hinge and reactive-centre loop, and the gene is not among the five C. elegans serpins established as bona fide inhibitors. The activity is ancestral to the nematode clade (a PAINT IBD at the nematode node, seeded by SRP-2) but this lineage has lost the structural element the activity depends on. No C28G1.2 inhibition assay exists, so this is a sequence-level refutation.
Supporting Evidence:

Deep Research

Falcon

(C28G1.2-deep-research-falcon.md)

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📚 Additional Documentation

Notes

(C28G1.2-notes.md)

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Bioinformatics Results

(RESULTS.md)

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Protnlm Function Review

(C28G1.2-protnlm-function-review.md)

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📄 View Raw YAML

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