CG43742

UniProt ID: A0A0B4KFF2
Organism: Drosophila melanogaster
Review Status: COMPLETE
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Gene Description

CG43742 (SP251) encodes a 474-residue secreted serine protease of the S1A (chymotrypsin-fold) family with two tandem trypsin-like domains and no clip domain. The N-terminal S1 domain (residues 35-258) retains the complete His73-Asp121-Ser207 catalytic triad, whereas the C-terminal S1 domain (282-472) lacks the catalytic histidine and serine motifs and is a non-catalytic protease-like domain. A predicted signal peptide (1-20) indicates secretion. Phylogenetically it groups with other long tandem-domain S1A proteins of Drosophila, including CG10764/SP77, within a fly-expanded protease subfamily. It is predicted to act as an extracellular serine endopeptidase, but its substrates, activating protease and physiological role have not been studied experimentally.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0003674 molecular_function
ND
GO_REF:0000015 		ACCEPT
Summary: Root molecular function ND annotation: when it was made, no molecular function had been curated for this gene product from literature.
Reason: ACCEPT under the ND acceptance rule (projects/NO_DATA.md). The evidence this review cites for the molecular function is inferred (from orthologs, family membership or sequence features) or comes from other species; none of it is literature on this gene product in this species. This was judged from the review's own content during the NO_DATA re-action pass, not from a new literature search. Earlier action: MODIFY. Re-checked 2026-10-31: PMID:30367934, cited in core_functions, is a computational survey of serine protease-related proteins. The gene's own literature-search record finds no study of this gene product in this species that identifies a molecular function.
Supporting Evidence:
file:DROME/CG43742/CG43742-deep-research-falcon.md
Catalytic activity, physiological substrate, subcellular/extracellular location, pathway membership, and mutant phenotype have not been experimentally established for this exact protein.
GO:0004252 serine-type endopeptidase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: The N-terminal domain supports serine-type endopeptidase activity.
Reason: The N-terminal S1 domain retains a complete His73-Asp121-Ser207 triad in TAAHC and DSGGP motifs, which supports serine-type endopeptidase activity for that domain. The second S1 domain lacks both the His and Ser motifs and is protease-like only. The chymotrypsin EC number behind this IEA (EC:3.4.21.1, PROSITE rule) is not evidence for a chymotrypsin-like P1 preference; only the broad GO term is accepted.
Supporting Evidence:
file:DROME/CG43742/CG43742-uniprot.txt
DR InterPro; IPR009003; Peptidase_S1_PA.
file:DROME/CG43742/CG43742-uniprot.txt
DR InterPro; IPR001314; Peptidase_S1A.
file:DROME/CG43742/CG43742-uniprot.txt
FT SIGNAL 1..20 FT /evidence="ECO:0000256|SAM:SignalP"
file:DROME/CG43742/CG43742-uniprot.txt
FT DOMAIN 35..258 FT /note="Peptidase S1" FT /evidence="ECO:0000259|PROSITE:PS50240"
PMID:30367934
SP49, SP77, SP222, SP248, and SP251 contain a PD and a PLD;
PMID: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
file:DROME/CG43742/CG43742-bioinformatics/RESULTS.md
S1 domain 1 (residues 35-258) carries H73 in a TAAHC motif, D121 and S207 in a DSGGP motif: the His-Asp-Ser triad is complete.
file:DROME/CG43742/CG43742-bioinformatics/RESULTS.md
so it is a protease-like domain that cannot be catalytic.
GO:0004252 serine-type endopeptidase activity
ISM
PMID:30367934
Building a platform for predicting functions of serine prote... 		ACCEPT
Summary: The sequence-based SP251 classification supports proteolytic potential.
Reason: PMID:30367934 explicitly places SP251 among proteins with a protease domain and a protease-like domain. This is comparative sequence evidence rather than a substrate assay; the exact source sequence retains the first-domain triad.
Supporting Evidence:
file:DROME/CG43742/CG43742-uniprot.txt
DR InterPro; IPR009003; Peptidase_S1_PA.
file:DROME/CG43742/CG43742-uniprot.txt
DR InterPro; IPR001314; Peptidase_S1A.
file:DROME/CG43742/CG43742-uniprot.txt
FT SIGNAL 1..20 FT /evidence="ECO:0000256|SAM:SignalP"
file:DROME/CG43742/CG43742-uniprot.txt
FT DOMAIN 35..258 FT /note="Peptidase S1" FT /evidence="ECO:0000259|PROSITE:PS50240"
PMID:30367934
SP49, SP77, SP222, SP248, and SP251 contain a PD and a PLD;
PMID: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
file:DROME/CG43742/CG43742-bioinformatics/RESULTS.md
S1 domain 1 (residues 35-258) carries H73 in a TAAHC motif, D121 and S207 in a DSGGP motif: the His-Asp-Ser triad is complete.
file:DROME/CG43742/CG43742-bioinformatics/RESULTS.md
so it is a protease-like domain that cannot be catalytic.
GO:0005575 cellular_component
ND
GO_REF:0000015 		ACCEPT
Summary: Root cellular component ND annotation: when it was made, no cellular component had been curated for this gene product from literature.
Reason: ACCEPT under the ND acceptance rule (projects/NO_DATA.md). The evidence this review cites for the cellular component is inferred (from orthologs, family membership or sequence features) or comes from other species; none of it is literature on this gene product in this species. This was judged from the review's own content during the NO_DATA re-action pass, not from a new literature search. Earlier action: MODIFY. Re-checked 2026-10-31: PMID:30367934, cited in core_functions, is a computational survey of serine protease-related proteins. The gene's own literature-search record finds no study of this gene product in this species that identifies a cellular location.
Supporting Evidence:
file:DROME/CG43742/CG43742-deep-research-falcon.md
Catalytic activity, physiological substrate, subcellular/extracellular location, pathway membership, and mutant phenotype have not been experimentally established for this exact protein.
GO:0005576 extracellular region
IBA
GO_REF:0000033 		ACCEPT
Summary: Extracellular localization is supported by architecture and phylogenetic inference.
Reason: The signal peptide and soluble tandem protease-domain architecture support the existing curated IBA extracellular annotation.
Propagation Review
Root cause: NO FAILURE CORE
Sources checked:
PANTHER:PTN000667087 SUPPORTS TRANSFER
PAINT places an Ecdysozoa-level extracellular-region assertion at this ancestor; CG43742 is below the node and retains a predicted signal peptide with no contrary localization evidence.
Supporting Evidence:
file:DROME/CG43742/CG43742-uniprot.txt
DR InterPro; IPR009003; Peptidase_S1_PA.
file:DROME/CG43742/CG43742-uniprot.txt
DR InterPro; IPR001314; Peptidase_S1A.
file:DROME/CG43742/CG43742-uniprot.txt
FT SIGNAL 1..20 FT /evidence="ECO:0000256|SAM:SignalP"
file:DROME/CG43742/CG43742-uniprot.txt
FT DOMAIN 35..258 FT /note="Peptidase S1" FT /evidence="ECO:0000259|PROSITE:PS50240"
PMID:30367934
SP49, SP77, SP222, SP248, and SP251 contain a PD and a PLD;
PMID: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
file:DROME/CG43742/CG43742-bioinformatics/RESULTS.md
The PANTHER 19.0 fruit-fly HMM classification assigns A0A0B4KFF2 to PTHR24260:SF147 (EG:BACR7A4.3 PROTEIN-RELATED)
GO:0006508 proteolysis
IEA
GO_REF:0000002 		ACCEPT
Summary: Proteolysis is the plausible core biochemical process.
Reason: The first S1 domain retains the annotated H-D-S triad and the second is protease-like. Broad proteolysis is supported without specifying cleavage targets or a developmental cascade.
Supporting Evidence:
file:DROME/CG43742/CG43742-uniprot.txt
DR InterPro; IPR009003; Peptidase_S1_PA.
file:DROME/CG43742/CG43742-uniprot.txt
DR InterPro; IPR001314; Peptidase_S1A.
file:DROME/CG43742/CG43742-uniprot.txt
FT SIGNAL 1..20 FT /evidence="ECO:0000256|SAM:SignalP"
file:DROME/CG43742/CG43742-uniprot.txt
FT DOMAIN 35..258 FT /note="Peptidase S1" FT /evidence="ECO:0000259|PROSITE:PS50240"
PMID:30367934
SP49, SP77, SP222, SP248, and SP251 contain a PD and a PLD;
PMID: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
file:DROME/CG43742/CG43742-bioinformatics/RESULTS.md
S1 domain 1 (residues 35-258) carries H73 in a TAAHC motif, D121 and S207 in a DSGGP motif: the His-Asp-Ser triad is complete.
GO:0008150 biological_process
ND
GO_REF:0000015 		ACCEPT
Summary: Root biological process ND annotation: when it was made, no biological process had been curated for this gene product from literature.
Reason: ACCEPT under the ND acceptance rule (projects/NO_DATA.md). The evidence this review cites for the biological process is inferred (from orthologs, family membership or sequence features) or comes from other species; none of it is literature on this gene product in this species. This was judged from the review's own content during the NO_DATA re-action pass, not from a new literature search. Earlier action: MODIFY. Re-checked 2026-10-31: PMID:30367934, cited in core_functions, is a computational survey of serine protease-related proteins. The gene's own literature-search record finds no study of this gene product in this species that identifies a biological process.
Supporting Evidence:
file:DROME/CG43742/CG43742-deep-research-falcon.md
Catalytic activity, physiological substrate, subcellular/extracellular location, pathway membership, and mutant phenotype have not been experimentally established for this exact protein.
GO:0008233 peptidase activity
IEA
GO_REF:0000104 		MODIFY
Summary: Serine-type endopeptidase activity is more specific than peptidase activity.
Reason: The S1 catalytic architecture supports the existing serine-type endopeptidase term.
Supporting Evidence:
file:DROME/CG43742/CG43742-uniprot.txt
DR InterPro; IPR009003; Peptidase_S1_PA.
file:DROME/CG43742/CG43742-uniprot.txt
DR InterPro; IPR001314; Peptidase_S1A.
file:DROME/CG43742/CG43742-uniprot.txt
FT SIGNAL 1..20 FT /evidence="ECO:0000256|SAM:SignalP"
file:DROME/CG43742/CG43742-uniprot.txt
FT DOMAIN 35..258 FT /note="Peptidase S1" FT /evidence="ECO:0000259|PROSITE:PS50240"
PMID:30367934
SP49, SP77, SP222, SP248, and SP251 contain a PD and a PLD;
PMID: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
file:DROME/CG43742/CG43742-bioinformatics/RESULTS.md
S1 domain 1 (residues 35-258) carries H73 in a TAAHC motif, D121 and S207 in a DSGGP motif: the His-Asp-Ser triad is complete.
GO:0016787 hydrolase activity
IEA
GO_REF:0000104 		MODIFY
Summary: Serine-type endopeptidase activity is more informative than hydrolase activity.
Reason: The first S1 domain and retained catalytic triad support the specific peptidase class rather than a generic hydrolase label.
Supporting Evidence:
file:DROME/CG43742/CG43742-uniprot.txt
DR InterPro; IPR009003; Peptidase_S1_PA.
file:DROME/CG43742/CG43742-uniprot.txt
DR InterPro; IPR001314; Peptidase_S1A.
file:DROME/CG43742/CG43742-uniprot.txt
FT SIGNAL 1..20 FT /evidence="ECO:0000256|SAM:SignalP"
file:DROME/CG43742/CG43742-uniprot.txt
FT DOMAIN 35..258 FT /note="Peptidase S1" FT /evidence="ECO:0000259|PROSITE:PS50240"
PMID:30367934
SP49, SP77, SP222, SP248, and SP251 contain a PD and a PLD;
PMID: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
file:DROME/CG43742/CG43742-bioinformatics/RESULTS.md
S1 domain 1 (residues 35-258) carries H73 in a TAAHC motif, D121 and S207 in a DSGGP motif: the His-Asp-Ser triad is complete.
GO:0045087 innate immune response
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Innate-immune participation is supported as a PAINT ancestral inference.
Reason: PAINT placed GO:0045087 at PTN000667087, an Ecdysozoa-level ancestor whose seeds are Drosophila and mosquito CLIP proteases of the Toll and melanization cascades (psh, MP1, spirit, SPE, grass, sphinx1/2, modSP). CG43742 descends from that node, so the IBA is a deliberate phylogenetic judgment and there is no target-specific evidence of loss. In PANTHER 19.0, however, CG43742 is classified in PTHR24260:SF147, which contains none of the seeds and also contains the developmental protease Snake; the nearest characterized relative on its tandem-domain branch, CG10764/SP77, is supported only by an RNAi encapsulation phenotype. The immune-process inference is therefore kept as a plausible but non-core, ancestral assertion.
Propagation Review
Root cause: NO FAILURE NON CORE
Sources checked:
PANTHER:PTN000667087 SUPPORTS TRANSFER
PAINT places an innate-immune assertion at the Ecdysozoa-level ancestor; CG43742 is below the node, though in PANTHER 19.0 it sits in subfamily SF147 that contains none of the experimental seeds. No target-specific loss or incompatible sequence change was found; the catalytic triad of domain 1 is intact.
Supporting Evidence:
file:DROME/CG43742/CG43742-bioinformatics/RESULTS.md
The PANTHER 19.0 fruit-fly HMM classification assigns A0A0B4KFF2 to PTHR24260:SF147 (EG:BACR7A4.3 PROTEIN-RELATED)
file:DROME/CG43742/CG43742-bioinformatics/RESULTS.md
all fall in other PTHR24260 subfamilies (SF134-SF145) in PANTHER 19.0, not in SF147.
PMID:33644706
CG10764 likely encodes an active serine protease, and may influence immune activation through the direct cleavage of target proteins.
GO:0051604 protein maturation
IEA
GO_REF:0000117 		MARK AS OVER ANNOTATED
Summary: Protein maturation is an ARBA association that asserts a processing role with no identified substrate.
Reason: This IEA comes only from an ARBA machine-learning rule (ARBA00026902). Protein maturation would require CG43742 to process a specific precursor (as Toll-pathway or prophenoloxidase-activating CLIP proteases do), and no substrate, cascade position or processing event is known for this protein. Generic proteolysis captures what its sequence supports; the more specific maturation process is an over-annotation.
Supporting Evidence:
file:DROME/CG43742/CG43742-bioinformatics/RESULTS.md
S1 domain 1 (residues 35-258) carries H73 in a TAAHC motif, D121 and S207 in a DSGGP motif: the His-Asp-Ser triad is complete.
file:DROME/CG43742/CG43742-uniprot.txt
PE 3: Inferred from homology;

Core Functions

Secreted serine endopeptidase whose N-terminal S1 domain carries an intact His-Asp-Ser catalytic triad, fused to a C-terminal non-catalytic protease-like domain; substrates and physiological process are unknown.

Molecular Function:
serine-type endopeptidase activity
Directly Involved In:
proteolysis
Cellular Locations:
extracellular region
Supporting Evidence:
  • file:DROME/CG43742/CG43742-bioinformatics/RESULTS.md
    S1 domain 1 (residues 35-258) carries H73 in a TAAHC motif, D121 and S207 in a DSGGP motif: the His-Asp-Ser triad is complete.
  • file:DROME/CG43742/CG43742-bioinformatics/RESULTS.md
    so it is a protease-like domain that cannot be catalytic.
  • PMID:30367934
    SP49, SP77, SP222, SP248, and SP251 contain a PD and a PLD;
  • file:DROME/CG43742/CG43742-uniprot.txt
    FT SIGNAL 1..20 FT /evidence="ECO:0000256|SAM:SignalP"

References

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Suggested Questions for Experts

Q: PANTHER 19.0 HMMs place CG43742 in PTHR24260:SF147 while UniProt and the GOA IBA rows use PTHR24256/PTN000667087; does the innate-immune IBA still hold once the PAINT tree is reconciled with the SF147 placement?

Q: Is CG43742 secreted into the hemolymph by the fat body, and which protease activates its zymogen?

Suggested Experiments

Experiment: Express recombinant CG43742 (wild type and S207A), activate it, and profile cleavage specificity on peptide libraries to test whether the N-terminal domain is an active endopeptidase.

Experiment: Make a CG43742 null allele and test larval hemolymph protease activity, melanization and survival after bacterial, fungal and parasitoid-wasp challenge, alongside CG10764 mutants.

Deep Research

Falcon

(CG43742-deep-research-falcon.md)

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📚 Additional Documentation

Notes

(CG43742-notes.md)

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Bioinformatics Results

(RESULTS.md)

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📄 View Raw YAML

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