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Tbio Tripeptidyl-peptidase 1

Lysosomal serine protease with tripeptidyl-peptidase I activity. May act as a non-specific lysosomal peptidase which generates tripeptides from the breakdown products produced by lysosomal proteinases. Requires substrates with an unsubstituted N-terminus (By similarity).

This gene encodes a member of the sedolisin family of serine proteases. The protease functions in the lysosome to cleave N-terminal tripeptides from substrates, and has weaker endopeptidase activity. It is synthesized as a catalytically-inactive enzyme which is activated and auto-proteolyzed upon acidification. Mutations in this gene result in late-infantile neuronal ceroid lipofuscinosis, which is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome. [provided by RefSeq, Jul 2008]

 Comments

Property Summary

NCBI Gene PubMed Count 87
PubMed Score 211.96
PubTator Score 238.17

Knowledge Summary

Patent

No data available

TINX Plot

  Disease (6)

Disease Target Count Z-score Confidence
Blindness 84 3.423 1.7

Expression

  Differential Expression (13)

Disease log2 FC p
astrocytoma 3.100 2.4e-03
ependymoma 1.600 9.1e-03
oligodendroglioma 2.200 6.7e-04
glioblastoma 2.100 2.2e-02
atypical teratoid / rhabdoid tumor 1.200 1.1e-03
acute quadriplegic myopathy 1.220 1.9e-05
tuberculosis 1.200 1.0e-06
pediatric high grade glioma 1.200 4.2e-03
group 3 medulloblastoma -1.300 8.6e-03
pilocytic astrocytoma 1.400 6.5e-06
Polycystic Ovary Syndrome -1.144 4.9e-02
ovarian cancer -2.800 7.5e-13
Down syndrome 2.100 2.0e-04

Synonym

Accession O14773 Q53HT1 Q5JAK6 Q6UX56 Q71JP6 Q96C37 TPP-1
Symbols CLN2
GIG1
LPIC
SCAR7
TPP-1

Gene

TPP1

PANTHER Protein Class (3)

PDB

1R60   3EDY   3EE6  

  Ortholog (1)

Species Source Disease
Chimp OMA EggNOG Inparanoid

 UniProt Keyword (22)

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 GO Function (7)

 GO Component (5)

 GO Process (11)

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 Compartment GO Term (34)

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 OMIM Phenotype (2)

 MGI Phenotype (8)

 HCA RNA Cell Line (56)

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Pathway (7)

Protein-protein Interaction (4)

RPTOR   SLC25A16   OMA1   NME4  

Gene RIF (54)

PMID Text
26503784 that the insertion in fingers domain can mediate enzyme processivity and telomerase recruitment to telomeres in a TPP1-dependent manner
26365187 The conservation between fission yeast Tpz1-Pot1 and human TPP1-POT1 interactions resulted in mapping a human melanoma-associated POT1 mutation (A532P) to the TPP1-POT1 interface.
25271372 Mutations have been identified in the TEN-domain of TERT that disrupt the interaction of telomerase with TPP1 in vivo and in vitro but have very little effect on the catalytic activity of telomerase.
25263700 these data provide a molecular basis by which POT1-TPP1 increases the processivity of telomerase15. Further, we show that this increased processivity may arise from the dynamic sliding of POT1-TPP1 that induces fast translocation of telomerase.
25172512 TPP1 is a binding partner and substrate for the deubiquitinating enzyme USP7.
25128433 TPP1 provides an essential step of telomerase activation as well as feedback regulation of telomerase by telomere length, which is necessary to determine the appropriate telomere length set point in human embryonic stem cells
24780581 TPP1 has recently emerged as a primary contributor in protecting telomere DNA and in recruiting telomerase to the telomere ends. (Review)
24516170 G-quadruplex formation of telomeres significantly enhances the ability of POT1/TPP1 to block RPA's access to telomeres.
24513288 Down-regulation of TPP1 induced cell apoptosis in telomerase-negative osteosarcoma cell line.
24271013 TPP1(CLN2) mutation is associated with neuronal ceroid lipofuscinosis.
24260532 Elevated expression of TPP1 in human colorectal cancer cells could protect telomere from DNA damage and confer radioresistance.
23862686 Telomere damage and reduced TPP1 dimerization as a result of Akt inhibition was also accompanied by diminished recruitment of TPP1 and POT1 to the telomeres.
23587805 TPP1 mutants utilize the advantages of a zebrafish model for understanding the pathogenesis of late infantile (or classic late infantile neuronal ceroid lipofuscinosis) disease.
23509301 Blocking TPP1 S111 phosphorylation by mutating residue S111 led to reduced telomerase association and telomere shortening.
23418007 hypothesize that loss of function variants abolishing TPP1 enzyme activity lead to CLN2 disease, whereas variants that diminish TPP1 enzyme activity lead to SCAR7
23266810 The variant juvenile phenotype comprises approximately 50% of CLN2 in South America. The five most frequent South American mutations comprise 66% of pathological alleles.
23249249 To our knowledge, our results bring the first evidence of a mechanism that links TPP-1 deficiency and oxidative stress-induced changes in mitochondrial morphology.
23103865 seven separation-of-function mutations map to a patch of amino acids on the surface of TPP1, the TEL patch, that both recruits telomerase to telomeres and promotes high-processivity DNA synthesis
22989886 Gemfibrozil and fenofibrate, Food and Drug Administration-approved lipid-lowering drugs, up-regulate tripeptidyl-peptidase 1 in brain cells via peroxisome proliferator-activated receptor alpha and may have implications in late infantile Batten disease therapy
22832778 This study demonistrated that the CLN2 gene 4 mutation in late infantile neuronal ceroid lipofuscinosis.
22016395 Studies indicate that TPP-I is the only member of the sedolisin family that has been shown to exhibit tripeptidyl peptidase activity and is related to the fatal hereditary disease, Batten disease.
21833529 Altered expression of TPP1 might contribute to persistent proliferation of fibroblast-like synovial cells in rheumatoid arthritis.
21829167 UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication
21784683 Intrathecal human tripeptidyl-peptidase 1 administration reduces lysosomal storage in a canine model of late infantile neuronal ceroid lipofuscinosis.
21461822 the human POT1-TPP1 complex is a processivity factor for telomerase
20689811 the critical residues in the TPPI catalysis and its structure-function analysis
20672930 The authors conducted a phase I study of late infantile neuronal ceroid lipofuscinosis using an adenoassociated virus serotype 2 (AAV2) vector containing the deficient CLN2 gene (AAV2(CU)hCLN2).
20340139 Data show that most TPPI variants displayed obstructed transport to the lysosomes.
19748052 This novel deletion mutation in the CLN2 gene in a family of Arab origin from Israel sheds further light on the epidemiology of neuronal ceroid lipofuscinosis as a worldwide disease
19246452 genetic deletion of the lysosomal serine protease CLN2 and the subsequent loss of its catalytic function confer resistance to TNF in non-neuronal somatic cells in a Bid-dependent manner, indicating that CLN2 plays a role in TNF-induced cell death
19201763 Observational study of gene-disease association. (HuGE Navigator)
19038967 Crystal structure and autoactivation pathway of the precursor form of human tripeptidyl-peptidase 1, the enzyme deficient in late infantile ceroid lipofuscinosis
19038966 Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis.
18552385 Lysosome-related genes, such as CLN2, CLN3, and HEXB, may be involved in the pathogenesis of adipose tissue hypertrophy in TED.
18411270 the tripeptidyl peptidase I prosegment is a potent, slow-binding inhibitor of its cognate enzyme
17959406 CLN2/TPP1 deficiency: the novel mutation IVS7-10A>G causes intron retention and is associated with a mild disease phenotype.
17690061 Clinical features, histological findings, and genetic study reveal that CLN2 type is the most common form of neuronal ceroid lipofuscinosis. There is male predominance of 90.1% in this part of the Arab world.
16518810 there is a close correlation between CLN2 and CLN1 expression and colorectal carcinoma progression and metastasis and suggest that they may be potential molecular targets
16168594 Mutational screening of CLCN2 gene, revealed a homozygous mutation G2003C (exon 17), leading to a Ser/Thr substitution at the codon 668, in two of the three in malignant migrating partial seizures patients.
16091586 Substrate-binding cleft of TPP-I composed of only 6 subsites; TPP-I prefers bulky and hydrophobic amino acid residues at P(1) position and Ala, Arg, or Asp at P(2) position; hydrophilic interactions at the S(2) subsite are necessary for TPP-I.
15733845 Ser475 and Asp360, also Glu272, Asp276, and Asp327 are important for catalytic activity of tripeptidyl peptidase I
15582991 tripeptidyl-peptidase I activation, activity, and stability are regulated by glycosaminoglycans
15317752 Functional analyses of CLN2 mutations reveal transport disruption of tripeptidyl-peptidase I to lysosomes.
15158442 TPP-I is the predominant proteolytic enzyme responsible for the intracellular degradation of neuromedin B
15143070 intramolecular (unimolecular) mechanism of TPP I activation and autoprocessing
14736728 mutant Asn286Ser CLN2 lacks one oligosaccharide chain resulting in enzymatic inactivation
14702339 human tripeptidyl-peptidase I must be N-glycosylated for folding, trafficking, and stability
12950156 CLN2 gene mutations may result in low cerebrospinal fluid pterin production in classical neuronal ceroid lipofuscinoses of late infantile onset.
12698559 a novel mutation in neuronal ceroid lipofuscinosis
12488460 human tripeptidyl-peptidase I is processed by a serine protease to the mature, active form in vivo
12376936 Missense mutations, R127Q, N286S, and T353P represent novel, previously not described alleles.
12134079 Data show that three neuronal ceroid lipofuscinoses disease forms with similar tissue pathology are connected at the molecular level: CLN5 polypeptides directly interact with the CLN2 and CLN3 proteins
12125808 The clinical, biochemical, and molecular genetic aspects of lysosomal storage disorders are discussed in this review
11462245 functional analysis of variants expressed in CHO cells

AA Sequence 

MGLQACLLGLFALILSGKCSYSPEPDQRRTLPPGWVSLGRADPEEELSLTFALRQQNVERLSELVQAVSD      1 - 70
PSSPQYGKYLTLENVADLVRPSPLTLHTVQKWLLAAGAQKCHSVITQDFLTCWLSIRQAELLLPGAEFHH     71 - 140
YVGGPTETHVVRSPHPYQLPQALAPHVDFVGGLHRFPPTSSLRQRPEPQVTGTVGLHLGVTPSVIRKRYN    141 - 210
LTSQDVGSGTSNNSQACAQFLEQYFHDSDLAQFMRLFGGNFAHQASVARVVGQQGRGRAGIEASLDVQYL    211 - 280
MSAGANISTWVYSSPGRHEGQEPFLQWLMLLSNESALPHVHTVSYGDDEDSLSSAYIQRVNTELMKAAAR    281 - 350
GLTLLFASGDSGAGCWSVSGRHQFRPTFPASSPYVTTVGGTSFQEPFLITNEIVDYISGGGFSNVFPRPS    351 - 420
YQEEAVTKFLSSSPHLPPSSYFNASGRAYPDVAALSDGYWVVSNRVPIPWVSGTSASTPVFGGILSLINE    421 - 490
HRILSGRPPLGFLNPRLYQQHGAGLFDVTRGCHESCLDEEVEGQGFCSGPGWDPVTGWGTPNFPALLKTL    491 - 560
LNP                                                                       561 - 563
//

Text Mined References (93)

PMID Year Title
26503784 2016 The Insertion in Fingers Domain in Human Telomerase Can Mediate Enzyme Processivity and Telomerase Recruitment to Telomeres in a TPP1-Dependent Manner.
26365187 2015 Dissecting Fission Yeast Shelterin Interactions via MICro-MS Links Disruption of Shelterin Bridge to Tumorigenesis.
25944712 2015 N-terminome analysis of the human mitochondrial proteome.
25271372 2014 Identification of human TERT elements necessary for telomerase recruitment to telomeres.
25263700 2014 Single-molecule real-time detection of telomerase extension activity.
25172512 2014 The shelterin component TPP1 is a binding partner and substrate for the deubiquitinating enzyme USP7.
25128433 2014 Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation.
24780581 2014 Multiple facets of TPP1 in telomere maintenance.
24516170 2014 G-quadruplex formation in telomeres enhances POT1/TPP1 protection against RPA binding.
24513288 2014 Suppression of telomere-binding protein TPP1 resulted in telomere dysfunction and enhanced radiation sensitivity in telomerase-negative osteosarcoma cell line.
24275569 2014 An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.
24271013 2014 Human iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway.
24260532 2013 Telomere-binding protein TPP1 modulates telomere homeostasis and confers radioresistance to human colorectal cancer cells.
23862686 2013 Akt regulates TPP1 homodimerization and telomere protection.
23587805 2013 A zebrafish model of CLN2 disease is deficient in tripeptidyl peptidase 1 and displays progressive neurodegeneration accompanied by a reduction in proliferation.
23533145 2013 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
23509301 2013 Phosphorylation of TPP1 regulates cell cycle-dependent telomerase recruitment.
23418007 2013 Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease).
23376485 2013 Proteomic analysis of podocyte exosome-enriched fraction from normal human urine.
23266810 2013 Neuronal ceroid lipofuscinosis type CLN2: a new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America.
23249249 2013 Different molecular mechanisms involved in spontaneous and oxidative stress-induced mitochondrial fragmentation in tripeptidyl peptidase-1 (TPP-1)-deficient fibroblasts.
23103865 2012 The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity.
22989886 2012 Gemfibrozil and fenofibrate, Food and Drug Administration-approved lipid-lowering drugs, up-regulate tripeptidyl-peptidase 1 in brain cells via peroxisome proliferator-activated receptor ?: implications for late infantile Batten disease therapy.
22832778 2013 Late infantile neuronal ceroid lipofuscinosis: mutations in the CLN2 gene and clinical course in Spanish patients.
22612257 2012 Targeted next generation sequencing as a diagnostic tool in epileptic disorders.
22016395 2012 New families of carboxyl peptidases: serine-carboxyl peptidases and glutamic peptidases.
21990111 2012 Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses.
21833529 2012 Altered expression of TPP1 in fibroblast-like synovial cells might be involved in the pathogenesis of rheumatoid arthritis.
21829167 2011 Human UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication.
21784683 2011 Intrathecal tripeptidyl-peptidase 1 reduces lysosomal storage in a canine model of late infantile neuronal ceroid lipofuscinosis.
21492153 2011 Analysis of proteomic changes induced upon cellular differentiation of the human intestinal cell line Caco-2.
21461822 2011 Human telomere POT1-TPP1 complex and its role in telomerase activity regulation.
21269460 2011 Initial characterization of the human central proteome.
20689811 2010 A critical tryptophan and Ca2+ in activation and catalysis of TPPI, the enzyme deficient in classic late-infantile neuronal ceroid lipofuscinosis.
20672930 2010 Gene therapy for late infantile neuronal ceroid lipofuscinosis: neurosurgical considerations.
20340139 2010 Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I.
19941651 2009 Novel interactions of CLN5 support molecular networking between Neuronal Ceroid Lipofuscinosis proteins.
19748052 2009 Late infantile neuronal ceroid lipofuscinosis: a new mutation in Arabs.
19246452 2009 Lysosomal serine protease CLN2 regulates tumor necrosis factor-alpha-mediated apoptosis in a Bid-dependent manner.
19201763 2009 Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis.
19159218 2009 Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry.
19056867 2009 Large-scale proteomics and phosphoproteomics of urinary exosomes.
19038967 2009 Crystal structure and autoactivation pathway of the precursor form of human tripeptidyl-peptidase 1, the enzyme deficient in late infantile ceroid lipofuscinosis.
19038966 2009 Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis.
18552385 2008 Lysosome-related genes are regulated in the orbital fat of patients with graves' ophthalmopathy.
18411270 2008 Prosegment of tripeptidyl peptidase I is a potent, slow-binding inhibitor of its cognate enzyme.
17959406 2008 CLN2/TPP1 deficiency: the novel mutation IVS7-10A>G causes intron retention and is associated with a mild disease phenotype.
17690061 2007 Late-infantile neuronal ceroid lipofuscinosis (CLN2/Jansky-Bielschowsky type) in Oman.
17081065 2006 Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes.
16518810 2006 Overexpression in colorectal carcinoma of two lysosomal enzymes, CLN2 and CLN1, involved in neuronal ceroid lipofuscinosis.
16168594 2006 Mutational scanning of potassium, sodium and chloride ion channels in malignant migrating partial seizures in infancy.
16091586 2005 Catalytic residues and substrate specificity of recombinant human tripeptidyl peptidase I (CLN2).
15733845 2005 Ser475, Glu272, Asp276, Asp327, and Asp360 are involved in catalytic activity of human tripeptidyl-peptidase I.
15582991 2005 Glycosaminoglycans modulate activation, activity, and stability of tripeptidyl-peptidase I in vitro and in vivo.
15520412 2004 A new locus for a childhood onset, slowly progressive autosomal recessive spinocerebellar ataxia maps to chromosome 11p15.
15489334 2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).
15342556 2004 Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions.
15317752 2004 Mutations in classical late infantile neuronal ceroid lipofuscinosis disrupt transport of tripeptidyl-peptidase I to lysosomes.
15158442 2004 The lysosomal degradation of neuromedin B is dependent on tripeptidyl peptidase-I: evidence for the impairment of neuropeptide degradation in late-infantile neuronal ceroid lipofuscinosis.
15143070 2004 Maturation of human tripeptidyl-peptidase I in vitro.
14736728 2004 Mutation of the glycosylated asparagine residue 286 in human CLN2 protein results in loss of enzymatic activity.
14702339 2004 N-glycosylation is crucial for folding, trafficking, and stability of human tripeptidyl-peptidase I.
14609438 2003 A model of tripeptidyl-peptidase I (CLN2), a ubiquitous and highly conserved member of the sedolisin family of serine-carboxyl peptidases.
12975309 2003 The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.
12950156 2003 R208X mutation in CLN2 gene associated with reduced cerebrospinal fluid pterins in a girl with classic late infantile neuronal ceroid lipofuscinosis.
12754519 2003 Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry.
12698559 [Tripeptidyl peptidase 1 deficiency in neuronal ceroid lipofuscinosis. A novel mutation].
12643545 Proteomic analysis of early melanosomes: identification of novel melanosomal proteins.
12488460 2003 Biosynthesis, glycosylation, and enzymatic processing in vivo of human tripeptidyl-peptidase I.
12477932 2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.
12414822 2002 Identification of novel CLN2 mutations shows Canadian specific NCL2 alleles.
12376936 2002 Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations.
12134079 2002 Neuronal ceroid lipofuscinoses are connected at molecular level: interaction of CLN5 protein with CLN2 and CLN3.
12125808 2002 Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes (CLN1 and CLN2).
11589012 2001 New mutations in the neuronal ceroid lipofuscinosis genes.
11462245 2001 Expression and analysis of CLN2 variants in CHO cells: Q100R represents a polymorphism, and G389E and R447H represent loss-of-function mutations.
11339651 Heterogeneity of late-infantile neuronal ceroid lipofuscinosis.
11241479 2001 Two novel CLN2 gene mutations in a Chinese patient with classical late-infantile neuronal ceroid lipofuscinosis.
11054422 2001 The human CLN2 protein/tripeptidyl-peptidase I is a serine protease that autoactivates at acidic pH.
10965052 2000 Tripeptidyl peptidase I, the late infantile neuronal ceroid lipofuscinosis gene product, initiates the lysosomal degradation of subunit c of ATP synthase.
10740217 2000 Batten's disease: clues to neuronal protein catabolism in lysosomes.
10737126 1998 Chromosomal localization of two genes underlying late-infantile neuronal ceroid lipofuscinosis.
10679303 2000 Characterization of endopeptidase activity of tripeptidyl peptidase-I/CLN2 protein which is deficient in classical late infantile neuronal ceroid lipofuscinosis.
10665500 2000 Prenatal testing for late infantile neuronal ceroid lipofuscinosis.
10617131 2000 Purification and characterization of bovine brain lysosomal pepstatin-insensitive proteinase, the gene product deficient in the human late-infantile neuronal ceroid lipofuscinosis.
10477428 1999 Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5.
10330339 1999 Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder.
9989590 1999 Classical late infantile neuronal ceroid lipofuscinosis fibroblasts are deficient in lysosomal tripeptidyl peptidase I.
9989235 1999 Tripeptidyl-peptidase I is apparently the CLN2 protein absent in classical late-infantile neuronal ceroid lipofuscinosis.
9653647 1998 Structural organization and sequence of CLN2, the defective gene in classical late infantile neuronal ceroid lipofuscinosis.
9295267 1997 Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis.
8215436 1993 Purification and characterization of a tripeptidyl peptidase I from human osteoclastomas: evidence for its role in bone resorption.
8125298 1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.