id: Q18287 gene_symbol: C28G1.2 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:6239 label: Caenorhabditis elegans 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: - term: id: GO:0005576 label: extracellular region evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - AGI_LocusCode:AT1G47710 - FB:FBgn0002930 - FB:FBgn0015586 - FB:FBgn0028984 - FB:FBgn0028986 - FB:FBgn0028990 - FB:FBgn0031973 - FB:FBgn0262057 - FB:FBgn0265137 - MGI:MGI:101780 - MGI:MGI:105045 - MGI:MGI:108080 - MGI:MGI:1913472 - MGI:MGI:1915304 - MGI:MGI:87963 - MGI:MGI:88278 - MGI:MGI:891968 - MGI:MGI:891969 - MGI:MGI:891970 - MGI:MGI:891971 - MGI:MGI:894696 - PANTHER:PTN000156123 - RGD:1306692 - RGD:1307404 - RGD:2069 - RGD:3249 - RGD:3326 - RGD:3747 - RGD:3748 - RGD:619833 - RGD:619896 - RGD:631369 - RGD:735225 - UniProtKB:P01008 - UniProtKB:P01009 - UniProtKB:P01011 - UniProtKB:P01014 - UniProtKB:P01019 - UniProtKB:P05121 - UniProtKB:P05154 - UniProtKB:P05155 - UniProtKB:P07093 - UniProtKB:P08697 - UniProtKB:P29508 - UniProtKB:P30740 - UniProtKB:P36955 - UniProtKB:P50453 - UniProtKB:Q7QIJ8 - UniProtKB:Q90935 - UniProtKB:Q95121 - UniProtKB:Q99574 - UniProtKB:Q9TTE1 review: action: 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 source_entities: - source_id: PANTHER:PTN000156123 source_label: PTHR11461 family root (Archaea-Eukaryota) source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET comment: 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). residue_claims_not_applicable: Localization claim; no catalytic or binding residue is involved. supported_by: - reference_id: PMID:25786854 supporting_text: 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. - reference_id: PMID:25786854 supporting_text: 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 - reference_id: PMID:14739286 supporting_text: they lack typical N-terminal signal peptides and reside intracellularly - reference_id: file:worm/C28G1.2/C28G1.2-bioinformatics/RESULTS.md supporting_text: Phobius predicts no signal peptide and no transmembrane segment. - reference_id: file:worm/C28G1.2/C28G1.2-bioinformatics/RESULTS.md supporting_text: PTN002479232 is a multifurcating duplication node whose children are the C. elegans/C. briggsae paralog lineages references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: PMID:10373004 title: Serpins in the Caenorhabditis elegans genome. findings: - statement: Primary comparative sequence analysis documents unusual nematode serpin architectures. The available abstract does not identify C28G1.2 specifically or demonstrate its function. supporting_text: 'Some appear complete, some show extensive deletions, and others appear to contain only the C-terminal part of the known serpin fold' full_text_unavailable: true reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract-only cache. Gives family context for divergent and truncated nematode serpins, which matches the compact architecture found for C28G1.2, but the abstract does not name C28G1.2. Relevance lowered from HIGH to MEDIUM in the 2026-10-21 re-review because it does not address this gene directly. No longer cited as support for the IBA row. - id: PMID:14739286 title: 'SRP-2 is a cross-class inhibitor that participates in postembryonic development of the nematode Caenorhabditis elegans: initial characterization of the clade L serpins.' findings: - statement: The C. elegans clade L serpins lack N-terminal signal peptides and are intracellular; SRP-2 is a cross-class inhibitor of granzyme B and lysosomal cathepsins. supporting_text: they lack typical N-terminal signal peptides and reside intracellularly - statement: The nine srp genes characterised in this study are a tandem array on chromosome V. C28G1.2 is on chromosome X, so it is not one of these nine genes. supporting_text: revealed nine serpin genes, tandemly arrayed on chromosome V full_text_unavailable: true reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract-only cache. Characterises the paralog SRP-2, which is the PAINT seed for the nematode inhibitor node. Its inhibitory activity is not transferred to C28G1.2, because C28G1.2 lacks the reactive-centre loop. - id: PMID:17889653 title: An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of lysosomal injury. findings: - statement: The paralog SRP-6 is an intracellular serpin that inhibits calpains and lysosomal cysteine peptidases and protects against necrosis. supporting_text: the C. elegans intracellular serpin, SRP-6, exhibits a prosurvival function by blocking necrosis full_text_unavailable: true reference_review: relevance: LOW correctness: VERIFIED review_notes: Paralog background only. Nothing in it is transferred to C28G1.2. - id: PMID:25786854 title: The aggregation-prone intracellular serpin SRP-2 fails to transit the ER in Caenorhabditis elegans. findings: - statement: C. elegans serpins lack signal peptides and are cytoplasmic. Only SRP-1, -2, -3, -6 and -7 are full-length inhibitors; the others are pseudogenes or noninhibitory variants. supporting_text: 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 reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text cached. This is the best experimental evidence on the localization of the clade to which C28G1.2 belongs. It does not name C28G1.2, so its applicability to this gene rests on the tree placement in the bioinformatics RESULTS. - id: file:worm/C28G1.2/C28G1.2-uniprot.txt title: UniProt sequence and serpin-domain annotation for Q18287 - id: file:worm/C28G1.2/C28G1.2-bioinformatics/RESULTS.md title: PANTHER tree placement, serpin architecture and signal-peptide analysis of C28G1.2 findings: - statement: C28G1.2 lacks the hinge and reactive-centre loop present in its inhibitory paralogs. supporting_text: In every local alignment, the paralog's hinge/reactive-centre-loop segment has no counterpart in Q18287 - statement: C28G1.2 sits within the Caenorhabditis intracellular serpin duplication clade and has no characterised ortholog. supporting_text: No ortholog outside Caenorhabditis was placed with it, so no experimentally characterised ortholog exists - id: file:worm/C28G1.2/C28G1.2-prediction-donor.json title: UniProt identification of the collagen-chaperone donor reference_review: relevance: NONE correctness: UNVERIFIED review_notes: Artifact of an earlier prediction-review pass. The 2026-10-21 re-review is independent of it, does not use it as evidence, and did not open it. Kept so that earlier citations still resolve. - id: file:worm/C28G1.2/C28G1.2-protnlm-source.json title: Frozen exact-input ProtNLM output and UniProt sequence for Q18287 reference_review: relevance: NONE correctness: UNVERIFIED review_notes: Machine-learning prediction output, not evidence. The 2026-10-21 re-review did not open or use it. Kept so that earlier citations still resolve. core_functions: [] suggested_questions: - question: >- 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? - question: Does purified C28G1.2 adopt a serpin fold, and does it bind any protease or other partner despite lacking a reactive-centre loop? - question: Is C28G1.2 expressed, and in which tissues and subcellular compartment? suggested_experiments: - description: >- 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. - description: >- 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.