tpp1 encodes lysosomal tripeptidyl-peptidase 1, a serine peptidase that sequentially removes N-terminal tripeptides from polypeptides during lysosomal proteolysis. Its activity supports normal neurodevelopment and locomotor function, and its deficiency causes neurodegeneration.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006508 proteolysis | IBA GO_REF:0000033 | ACCEPT | Summary: proteolysis (GO:0006508) is supported for Tpp1. Falcon deep research confirms zebrafish Tpp1 is a lysosomal sedolisin-family serine protease contributing to lysosomal proteolysis/proteostasis. Reason: Tpp1 is a lysosomal serine tripeptidyl-peptidase acting in proteolysis. Supporting Evidence: file:DANRE/tpp1/tpp1-uniprot.txt Lysosomal serine protease with tripeptidyl-peptidase I file:DANRE/tpp1/tpp1-uniprot.txt Release of an N-terminal tripeptide file:DANRE/tpp1/tpp1-uniprot.txt SUBCELLULAR LOCATION: Lysosome PMID:23587805 deficient in tripeptidyl peptidase 1 file:DANRE/tpp1/tpp1-deep-research-falcon.md Tpp1 contributes to **lysosomal proteolysis/proteostasis** |
| GO:0008240 tripeptidyl-peptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: tripeptidyl-peptidase activity (GO:0008240) is supported for Tpp1 and is its core molecular function. Falcon deep research confirms zebrafish Tpp1 acts mainly as an N-terminal exopeptidase releasing tripeptides, assayed with the fluorogenic substrate Arg-Ala-Phe-ACC at acidic pH. Reason: Tpp1 is a lysosomal serine tripeptidyl-peptidase acting in proteolysis. Supporting Evidence: file:DANRE/tpp1/tpp1-uniprot.txt Lysosomal serine protease with tripeptidyl-peptidase I file:DANRE/tpp1/tpp1-uniprot.txt Release of an N-terminal tripeptide file:DANRE/tpp1/tpp1-uniprot.txt SUBCELLULAR LOCATION: Lysosome PMID:23587805 deficient in tripeptidyl peptidase 1 file:DANRE/tpp1/tpp1-deep-research-falcon.md tpp1 encodes lysosomal tripeptidyl-peptidase 1 (EC 3.4.14.9), a sedolisin-family serine protease that acts mainly as an **N-terminal exopeptidase** file:DANRE/tpp1/tpp1-deep-research-falcon.md cleavage of the fluorogenic tripeptidyl substrate **Arg-Ala-Phe-ACC** at **acidic pH (pH 4.0)** |
| GO:0004175 endopeptidase activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: endopeptidase activity (GO:0004175) is a supported but broad parent term for Tpp1. Falcon deep research confirms Tpp1 acts mainly as an N-terminal exopeptidase with only limited endopeptidase activity, so this broad term is retained as non-core. Reason: The more informative tripeptidyl-peptidase and serine-type peptidase activities are reviewed separately; this parent term is retained as non-core to reduce redundancy. Supporting Evidence: file:DANRE/tpp1/tpp1-uniprot.txt Lysosomal serine protease with tripeptidyl-peptidase I file:DANRE/tpp1/tpp1-uniprot.txt Release of an N-terminal tripeptide file:DANRE/tpp1/tpp1-uniprot.txt SUBCELLULAR LOCATION: Lysosome PMID:23587805 deficient in tripeptidyl peptidase 1 file:DANRE/tpp1/tpp1-deep-research-falcon.md removing **tripeptides** from the N-termini of polypeptide substrates, with some **limited endopeptidase activity** |
| GO:0007417 central nervous system development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: central nervous system development (GO:0007417) is supported as a phenotype of Tpp1 deficiency but is not the core molecular role. Falcon deep research describes early-onset progressive neurodegeneration of the retina, optic tectum and cerebellum in tpp1 mutants, consistent with a downstream consequence of impaired lysosomal proteolysis. Reason: The direct conserved role is lysosomal tripeptidyl-peptidase/proteolysis; neurodevelopmental and locomotor defects are downstream phenotypes. Supporting Evidence: PMID:23587805 displays progressive neurodegeneration PMID:23587805 functional motor impairment file:DANRE/tpp1/tpp1-deep-research-falcon.md early-onset, progressive neurodegenerative phenotype with prominent defects in **retina**, **optic tectum**, and **cerebellum** |
| GO:0004252 serine-type endopeptidase activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: serine-type endopeptidase activity (GO:0004252) is a broad term for Tpp1 that asserts endopeptidase specificity. Falcon deep research confirms Tpp1 is a serine protease with a sedolisin-family catalytic triad (Glu-Asp-Ser), but it acts mainly as an N-terminal exopeptidase with only limited endopeptidase activity. This IEA annotation derives from the Peptidase_S8/S53 superfamily fold (InterPro IPR036852), which spans both endo- and exo-peptidases, so the automatic domain mapping does not accurately reflect CLN2/Tpp1's primary exopeptidase specificity. The serine-type peptidase activity (GO:0008236) parent is more accurate, and the specific tripeptidyl-peptidase activity (GO:0008240) is the core function. Retained as non-core, consistent with the endopeptidase activity (GO:0004175) parent term. Reason: Tpp1 is primarily an exopeptidase with only limited endopeptidase activity; this endopeptidase-specific IEA term (from the broad Peptidase_S8/S53 fold) overstates the specificity and is retained as non-core, consistent with the GO:0004175 endopeptidase activity parent. Supporting Evidence: file:DANRE/tpp1/tpp1-uniprot.txt Lysosomal serine protease with tripeptidyl-peptidase I file:DANRE/tpp1/tpp1-uniprot.txt Release of an N-terminal tripeptide file:DANRE/tpp1/tpp1-uniprot.txt SUBCELLULAR LOCATION: Lysosome PMID:23587805 deficient in tripeptidyl peptidase 1 file:DANRE/tpp1/tpp1-deep-research-falcon.md removing **tripeptides** from the N-termini of polypeptide substrates, with some **limited endopeptidase activity** file:DANRE/tpp1/tpp1-deep-research-falcon.md catalytic triad consistent with sedolisin-family enzymes (reported as **Glu–Asp–Ser** |
| GO:0005764 lysosome | IEA GO_REF:0000044 | ACCEPT | Summary: lysosome (GO:0005764) is supported for Tpp1. Falcon deep research confirms the enzyme is targeted to and functions in the lysosome, predicted to be delivered after removal of a 19-aa signal peptide via the mannose-6-phosphate pathway. Reason: Tpp1 is a lysosomal serine tripeptidyl-peptidase acting in proteolysis. Supporting Evidence: file:DANRE/tpp1/tpp1-uniprot.txt Lysosomal serine protease with tripeptidyl-peptidase I file:DANRE/tpp1/tpp1-uniprot.txt Release of an N-terminal tripeptide file:DANRE/tpp1/tpp1-uniprot.txt SUBCELLULAR LOCATION: Lysosome PMID:23587805 deficient in tripeptidyl peptidase 1 file:DANRE/tpp1/tpp1-deep-research-falcon.md the enzyme is targeted to and functions in the **lysosome** |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | ACCEPT | Summary: proteolysis (GO:0006508) is supported for Tpp1 (InterPro-derived). Falcon deep research confirms Tpp1 contributes to lysosomal proteolysis/proteostasis; loss yields lysosomal storage of undegraded material. Note that the more specific GO:1905146 (lysosomal protein catabolic process) would more precisely capture Tpp1's biological role within the lysosome; GO:0006508 is retained here as the directly annotated, conservative term. Reason: Tpp1 is a lysosomal serine tripeptidyl-peptidase acting in proteolysis. Supporting Evidence: file:DANRE/tpp1/tpp1-uniprot.txt Lysosomal serine protease with tripeptidyl-peptidase I file:DANRE/tpp1/tpp1-uniprot.txt Release of an N-terminal tripeptide file:DANRE/tpp1/tpp1-uniprot.txt SUBCELLULAR LOCATION: Lysosome PMID:23587805 deficient in tripeptidyl peptidase 1 file:DANRE/tpp1/tpp1-deep-research-falcon.md Tpp1 contributes to **lysosomal proteolysis/proteostasis** |
| GO:0008236 serine-type peptidase activity | IEA GO_REF:0000002 | MODIFY | Summary: serine-type peptidase activity (GO:0008236) is correct but less specific than tripeptidyl-peptidase activity. Falcon deep research confirms the informative function is N-terminal tripeptidyl exopeptidase cleavage, so the more specific GO:0008240 is preferred. Reason: The specific molecular function is tripeptidyl-peptidase activity. Proposed replacements: tripeptidyl-peptidase activity Supporting Evidence: file:DANRE/tpp1/tpp1-uniprot.txt Lysosomal serine protease with tripeptidyl-peptidase I file:DANRE/tpp1/tpp1-uniprot.txt Release of an N-terminal tripeptide file:DANRE/tpp1/tpp1-uniprot.txt SUBCELLULAR LOCATION: Lysosome PMID:23587805 deficient in tripeptidyl peptidase 1 file:DANRE/tpp1/tpp1-deep-research-falcon.md tpp1 encodes lysosomal tripeptidyl-peptidase 1 (EC 3.4.14.9), a sedolisin-family serine protease that acts mainly as an **N-terminal exopeptidase** |
| GO:0005764 lysosome | ISS GO_REF:0000024 | ACCEPT | Summary: lysosome (GO:0005764) is supported for Tpp1 by orthology to human TPP1/O14773. Falcon deep research corroborates lysosomal localization, with loss producing enlarged/hypertrophic lysosomes and SCMAS storage. Reason: Tpp1 is a lysosomal serine tripeptidyl-peptidase acting in proteolysis. Supporting Evidence: file:DANRE/tpp1/tpp1-uniprot.txt Lysosomal serine protease with tripeptidyl-peptidase I file:DANRE/tpp1/tpp1-uniprot.txt Release of an N-terminal tripeptide file:DANRE/tpp1/tpp1-uniprot.txt SUBCELLULAR LOCATION: Lysosome PMID:23587805 deficient in tripeptidyl peptidase 1 file:DANRE/tpp1/tpp1-deep-research-falcon.md lysosomal storage phenotypes including **enlarged/hypertrophic lysosomes** |
| GO:0007417 central nervous system development | IMP PMID:23587805 A zebrafish model of CLN2 disease is deficient in tripeptidy... | KEEP AS NON CORE | Summary: central nervous system development (GO:0007417) is supported as a phenotype of Tpp1 deficiency (zebrafish IMP) but is not the core molecular role. Falcon deep research describes progressive neurodegeneration of the retina, optic tectum and cerebellum in tpp1 mutants. Reason: The direct conserved role is lysosomal tripeptidyl-peptidase/proteolysis; neurodevelopmental and locomotor defects are downstream phenotypes. Supporting Evidence: PMID:23587805 displays progressive neurodegeneration PMID:23587805 functional motor impairment file:DANRE/tpp1/tpp1-deep-research-falcon.md early-onset, progressive neurodegenerative phenotype with prominent defects in **retina**, **optic tectum**, and **cerebellum** |
| GO:0007626 locomotory behavior | IMP PMID:23587805 A zebrafish model of CLN2 disease is deficient in tripeptidy... | KEEP AS NON CORE | Summary: locomotory behavior (GO:0007626) is supported as a phenotype of Tpp1 deficiency (zebrafish IMP) but is not the core molecular role. Falcon deep research notes a phase of increased locomotion consistent with seizures followed by progressive motor impairment. Reason: The direct conserved role is lysosomal tripeptidyl-peptidase/proteolysis; neurodevelopmental and locomotor defects are downstream phenotypes. Supporting Evidence: PMID:23587805 displays progressive neurodegeneration PMID:23587805 functional motor impairment file:DANRE/tpp1/tpp1-deep-research-falcon.md phase of **increased locomotion consistent with seizures** |
| GO:0022008 neurogenesis | IMP PMID:23587805 A zebrafish model of CLN2 disease is deficient in tripeptidy... | KEEP AS NON CORE | Summary: neurogenesis (GO:0022008) is supported as a phenotype of Tpp1 deficiency (zebrafish IMP) but is not the core molecular role. PMID:23587805 reports that secondary neurogenesis in the retina, optic tectum and cerebellum is impaired in tpp1 mutant zebrafish, and falcon deep research notes a sustained reduction in proliferation affecting the retina and midbrain-hindbrain boundary. Reason: The direct conserved role is lysosomal tripeptidyl-peptidase/proteolysis; neurodevelopmental and locomotor defects are downstream phenotypes. Supporting Evidence: PMID:23587805 Secondary neurogenesis in the file:DANRE/tpp1/tpp1-deep-research-falcon.md **sustained reduction in proliferation** |
| GO:0008240 tripeptidyl-peptidase activity | ISS PMID:14609438 A model of tripeptidyl-peptidase I (CLN2), a ubiquitous and ... | ACCEPT | Summary: tripeptidyl-peptidase activity (GO:0008240) is supported for Tpp1 by sequence similarity to the highly conserved sedolisin-family CLN2/TPP-I enzymes. Falcon deep research confirms zebrafish Tpp1 acts mainly as an N-terminal exopeptidase releasing tripeptides. Reason: Tpp1 is a lysosomal serine tripeptidyl-peptidase acting in proteolysis. Supporting Evidence: file:DANRE/tpp1/tpp1-uniprot.txt Lysosomal serine protease with tripeptidyl-peptidase I file:DANRE/tpp1/tpp1-uniprot.txt Release of an N-terminal tripeptide file:DANRE/tpp1/tpp1-uniprot.txt SUBCELLULAR LOCATION: Lysosome PMID:23587805 deficient in tripeptidyl peptidase 1 file:DANRE/tpp1/tpp1-deep-research-falcon.md removing **tripeptides** from the N-termini of polypeptide substrates, with some **limited endopeptidase activity** |
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Download this section (compressed HTML)Q: Which endogenous lysosomal substrates require zebrafish Tpp1-mediated removal of N-terminal tripeptides, and which accumulate as storage material when the enzyme is absent?
Q: Does zebrafish Tpp1 require autocatalytic activation of its zymogen at acidic lysosomal pH, mirroring the proenzyme maturation described for mammalian TPP-I/CLN2?
Q: To what extent do the neurodegenerative and locomotor phenotypes of Tpp1-deficient zebrafish stem from impaired lysosomal proteolysis versus secondary consequences of ceroid-lipofuscin storage?
Experiment: Generate a tpp1 null line by CRISPR/Cas9, then assay lysosomal tripeptidyl-peptidase activity in larval/adult brain lysates against a fluorogenic Ala-Ala-Phe substrate and quantify ceroid-lipofuscin storage histologically.
Hypothesis: Loss of zebrafish tpp1 abolishes lysosomal tripeptidyl-peptidase activity and leads to accumulation of autofluorescent storage material in neurons.
Type: CRISPR knockout
Experiment: Express and purify the Tpp1 proenzyme, incubate across a range of pH values (acidic lysosomal versus neutral), and monitor proteolytic processing and gain of exopeptidase activity over time by SDS-PAGE and activity assays.
Hypothesis: Recombinant zebrafish Tpp1 is produced as an inactive zymogen that undergoes autocatalytic activation upon exposure to acidic pH.
Type: tripeptidyl-peptidase activity assay
Experiment: Reintroduce wild-type or catalytically dead tpp1 mRNA/transgene into tpp1 mutants and assess rescue of progressive neurodegeneration, neuronal proliferation, and swimming behavior alongside lipofuscin storage load.
Hypothesis: Restoring Tpp1 enzymatic activity in tpp1-deficient zebrafish rescues neurodegeneration and locomotor defects.
Type: lipofuscin/storage-material histology
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