CG17404 (Q9VGC0): evidence and ProtNLM claim review

CG17404 is a predicted secreted S1-family serine endopeptidase also known as SP149. Its catalytic histidine-aspartate-serine triad is retained, supporting proteolytic potential. Chymotrypsin-like substrate preference and specific equivalence to mammalian CTRL remain unresolved.

Exact input: Q9VGC0, 275 residues. The accession was fetched explicitly with the gene-directory alias; no canonical-sequence substitution is made.

Raw emitted predictions: CG17404-predictions-source.json. Source features: CG17404-uniprot.txt, with an exact extraction in CG17404-sequence-evidence.json.

Sequence and domain evidence

These are sequence/domain observations or explicitly named feature predictions, not measurements of biological function. ARBA assertions and ProtNLM-derived UniProt names are not counted as validation.

DR   InterPro; IPR009003; Peptidase_S1_PA.
DR   InterPro; IPR001314; Peptidase_S1A.
DR   InterPro; IPR051487; Ser/Thr_Proteases_Immune/Dev.
DR   InterPro; IPR001254; Trypsin_dom.
DR   InterPro; IPR018114; TRYPSIN_HIS.
DR   InterPro; IPR033116; TRYPSIN_SER.
FT   SIGNAL          1..20
FT                   /evidence="ECO:0000256|SAM:SignalP"
FT   DOMAIN          35..274
FT                   /note="Peptidase S1"
FT                   /evidence="ECO:0000259|PROSITE:PS50240"
FT   ACT_SITE        80
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000256|PROSITE-ProRule:PRU00274"
FT   ACT_SITE        124
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000256|PROSITE-ProRule:PRU00274"
FT   ACT_SITE        225
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000256|PROSITE-ProRule:PRU00274"

At the annotated catalytic positions, direct indexing of the exact sequence gives: H80, D124, S225. These positions come from PROSITE features, not a new alignment; no substrate preference or assay result is inferred.

ProtNLM claims

The snapshot emits names and location/keyword statements, with no GO or EC prediction for this target. Each actual statement is assessed below; no GO term has been substituted for it. Categories follow the function-prediction rubric, with nonspecific “uncharacterized” names marked UNC because they contain no testable function. CNN records an independently supported existing annotation; it does not assert a particular training-set composition.

Kind	Verbatim emitted statement	Assessment	Evidence and limitation
Name	Chymotrypsin-like protease CTRL-1	UNC	The exact target supports a serine-protease family assignment but not equivalence to human CTRL/P40313 or its substrate preference. A similarity-derived name and PROSITE class prediction do not resolve paralog-specific specificity.
Location	Secreted (SL-0243)	CNN	A SignalP signal peptide at residues 1-20 and soluble mature S1 architecture support secretion, consistent with the curated extracellular annotation.

Literature evidence

PMID:30367934(https://pubmed.ncbi.nlm.nih.gov/30367934/): “The SP-related sequences in each species were divided into SPs or SPHs based on the presence or absence of the His-Asp-Ser catalytic triad”

Annotation decisions

GO:0004252 serine-type endopeptidase activity (IBA): ACCEPT. The S1 domain retains annotated H80 D124 S225, consistent with the existing phylogenetic activity inference.
GO:0004252 serine-type endopeptidase activity (IEA): ACCEPT. The exact catalytic residues are retained; the narrower chymotrypsin name is not required to justify GO:0004252.
GO:0004252 serine-type endopeptidase activity (ISM): ACCEPT. PMID:12568721 is a comparative Drosophila SP/SPH analysis. Its abstract does not establish substrate specificity; the exact record independently retains the annotated catalytic H-D-S residues.
GO:0004252 serine-type endopeptidase activity (ISM): ACCEPT. PMID:30367934 separates catalytic proteases from homologs by H-D-S conservation. The annotated catalytic sites in the target retain all three residue types.
GO:0005576 extracellular region (IBA): ACCEPT. A SignalP signal peptide at residues 1-20 and a soluble S1-domain architecture support the curated IBA location.
GO:0006508 proteolysis (IBA): ACCEPT. The intact catalytic triad supports proteolytic potential without identifying a substrate or tissue-specific pathway.
GO:0006508 proteolysis (IEA): ACCEPT. The exact S1 domain retains annotated catalytic residues rather than merely a protease-like fold.
GO:0006508 proteolysis (ISM): ACCEPT. PMID:12568721 provides an SP/SPH classification framework and the exact target retains its annotated H-D-S catalytic triad; this is inferential evidence rather than a substrate assay.
GO:0008233 peptidase activity (IEA): MODIFY. S1 architecture with annotated catalytic H80 D124 S225 supports the specific enzyme class.
GO:0016787 hydrolase activity (IEA): MODIFY. The S1 catalytic architecture supports serine-type endopeptidase activity.

Research provenance

Genuine external literature research is requested through the repository Falcon wrapper, with perplexity-lite configured as fallback. Provider output is retained separately as CG17404-deep-research-<provider>.md; its source leads are checked against the underlying publications and exact sequence record.

2026-10-21 — Full re-review, independent of the ProtNLM2 predictions

This re-review ignores all ProtNLM/ProtNLM2 output, including the table above. Inputs were the UniProt record, the GOA rows, the cached publications (PMID:12568721 abstract only; PMID:30367934 full text), the existing falcon deep-research report, and two new analyses in CG17404-bioinformatics/ (check_sequence_rereview.py and panther_tree_rereview.py, summarised in RESULTS-rereview.md).

Identity

Q9VGC0 is the only UniProt product of FBgn0038001 (CG17404/SP149): 275 aa, sequence version 3, unreviewed (PE 3). It is the full-length product with signal peptide, propeptide and complete S1 domain. It is not a fragment, isoform or alternative gene model.

Sequence findings

Catalytic triad intact: His80 (TAAHC), Asp124, Ser225 in GDSGGP.
The protein is single-domain. Only 14 residues (no Cys) separate the signal peptide (1-20) from the S1 domain (35-274), so there is no clip domain. The UniProt "CLIP subfamily" similarity note (ARBA only) and the deep-research text that follows it do not fit the sequence.
Predicted zymogen activation at R34-I35 (IVGG mature N terminus).
S1-pocket position 189 (chymotrypsin numbering) is Gly, not the Asp of trypsins. This does not by itself support the chymotrypsin (EC 3.4.21.1) name, which comes from a PROSITE rule. Specificity is left unresolved.

Evolutionary placement

PANTHER PTHR24256:SF562 (IP09525P-RELATED). The clade PTN009088600 (Eumetazoa) has 8 leaves: CG17404, CG12256 and CG3916 (an in-Drosophila tandem duplication, FBgn0038001-3), plus one Anopheles, two Tribolium and two Trichoplax genes. There is no vertebrate member and no characterised member.
SF562 branches directly from the Eumetazoa duplication node PTN001207268, which carries the IBD assertions for GO:0004252, GO:0006508 and GO:0005576. The sister clades are PTN007783152 (mammalian tryptases plus Drosophila Easter, Sp7 and CLIP SPs) and PTN009088603 (PRSS21/testisin and many Drosophila SPHs). All characterised relatives are therefore equidistant paralogs, and none of their clade-specific functions transfers.
The PAINT NOT GO:0004252 (IKR) nodes all fall on other SPH lineages, none on the Q9VGC0 lineage.

Annotation decisions (re-review)

GO:0004252 serine-type endopeptidase activity (IBA, IEA, ISM x2): ACCEPT. Root-node IBD, no negation on the lineage, intact triad.
GO:0005576 extracellular region (IBA): ACCEPT. Signal peptide, soluble architecture.
GO:0006508 proteolysis (IBA, IEA, ISM): ACCEPT. This is the most specific process supported. Easter (dorsoventral patterning), Sp7 (melanization) and tryptase processes are not transferred.
GO:0008233 peptidase activity, GO:0016787 hydrolase activity (IEA): MODIFY to GO:0004252.
No NEW terms proposed.
The description was rewritten to remove the CTRL-equivalence wording, which came from the ProtNLM name. Core function: GO:0004252 in GO:0005576, directly involved in GO:0006508. Added a BP_DARK knowledge gap, suggested questions and suggested experiments.

Relative for follow-up

There is no characterised ortholog. The nearest characterised relative chosen is Drosophila Easter (ea, P13582, FBgn0000533). It sits in sister clade PTN007783152 and is an experimental donor for all three PTN001207268 IBD terms. It is a paralog at the Eumetazoa duplication; it is closer in phylogenetic standing, though not in tree distance, than the mammalian tryptases. No review of ea exists in the repo.

Family review and modules

interpro/panther/PTHR24256/PTHR24256-review.yaml lists Q9VGC0 under "Benchmark members without resolved subfamily placement". PANTHER 19.0 resolves it to SF562, together with CG12256 and CG3916. The review's summary calls PTHR24256 an "insect protease-related family", but the family also contains the mammalian tryptases and PRSS21. Neither point changes the annotations here.
No module in modules/ or GO-CAM in gocams/index.tsv includes CG17404.