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Gene Review

TPP1  -  tripeptidyl peptidase I

Homo sapiens

Synonyms: CLN2, Cell growth-inhibiting gene 1 protein, GIG1, LPIC, Lysosomal pepstatin-insensitive protease, ...
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Disease relevance of TPP1


Psychiatry related information on TPP1


High impact information on TPP1

  • They are interconnected by three additional shelterin proteins, TIN2, TPP1, and Rap1, forming a complex that allows cells to distinguish telomeres from sites of DNA damage [11].
  • Conversely, knocking down TPP1 reduced the ability of endogenous TRF1 to associate with the TRF2 complex [12].
  • In 14 patients, CLN2 protease activities were normal and no mutations were identified, suggesting other forms of NCL [13].
  • The late-infantile form of neuronal ceroid lipofuscinosis (LINCL) is a progressive and ultimately fatal neurodegenerative disease of childhood [13].
  • The defective gene in this hereditary disorder, CLN2, encodes a recently identified lysosomal pepstatin-insensitive acid protease [13].

Chemical compound and disease context of TPP1

  • Classical late-infantile neuronal ceroid lipofuscinosis (LINCL), a progressive and fatal neurodegenerative disease of childhood, results from mutations in a gene (CLN2) that encodes a protein with significant sequence similarity to prokaryotic pepstatin-insensitive acid proteases [14].
  • In the current study, using subtraction cloning for genes that are differentially expressed in metastasis, the authors isolated a clone encoding ceroid lipofuscinosis, neuronal 2 (CLN2), which is a lysosomal serine protease defective in neuronal ceroid lipofuscinosis (NCL) [15].
  • Tripeptidyl peptidase I (TTP-I), also known as CLN2, a member of the family of serine-carboxyl proteinases (S53), plays a crucial role in lysosomal protein degradation and a deficiency in this enzyme leads to fatal neurodegenerative disease [16].

Biological context of TPP1


Anatomical context of TPP1


Associations of TPP1 with chemical compounds

  • CLN1 and CLN2 are caused by mutations in genes that encodes lysosomal enzymes,palmitoyl protein thioesterase and pepstatin-insensitive proteinase, respectively [25].
  • The genes CLN1 and CLN2 encode lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase 1 [8].
  • Flupirtine also prevents the death of CLN3- and CLN2-deficient postmitotic hNT neurons at the mitochondrial level [20].
  • A specific inhibitor of TPP-I is able to abolish neuromedin B degradation in a variety of cell types [2].
  • These data indicate that the CLN2 gene product is synthesized as an inactive proenzyme that is autocatalytically converted to an active serine protease [3].

Physical interactions of TPP1

  • The major storage component in CLN2 is the subunit c of mitochondrial ATP synthase complex and its accumulation is the direct result of lack of CLN2p in this disease [25].
  • TPP1 is a previously identified binding partner of POT1 that has been proposed to form part of a six-protein shelterin complex at telomeres [26].
  • The POT1-TPP1 telomere complex is a telomerase processivity factor [26].

Other interactions of TPP1

  • Only products of two of these genes, CLN 1 and CLN2, have structural and functional properties of lysosomal enzymes [27].
  • Previously, diagnosis of NCL was based on age at onset and clinicopathologic (C-P) findings, classified as 1) infantile (INCL), 2) late infantile (LINCL), 3) juvenile (JNCL), and 4) adult (ANCL) [8].
  • Analysis of a further 33 classical LINCL families supported linkage in this region (Zmax = 3.07 at theta = 0.06 at D11S1338) [18].
  • Accumulation of subunit c of mitochondrial ATP synthase, to curvilinear profiles, is found in LINCL cases [28].
  • Extensive neuronal death is seen in CLN2- and CLN3-deficient human brain as well as in CLN6-deficient sheep brain and retina [20].
  • Noteworthy, correction of the lysosomal enzyme defect of LINCL fibroblasts using a medium enriched in CLN2 protein enabled restoration of TNF-induced Bid and caspase-3 processing and toxicity [29].

Analytical, diagnostic and therapeutic context of TPP1


  1. Molecular diagnosis of and carrier screening for the neuronal ceroid lipofuscinoses. Zhong, N.A., Wisniewski, K.E., Ju, W., Moroziewicz, D.N., Jurkiewicz, A., McLendon, L., Jenkins, E.C., Brown, W.T. Genet. Test. (2000) [Pubmed]
  2. 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. Kopan, S., Sivasubramaniam, U., Warburton, M.J. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  3. The human CLN2 protein/tripeptidyl-peptidase I is a serine protease that autoactivates at acidic pH. Lin, L., Sohar, I., Lackland, H., Lobel, P. J. Biol. Chem. (2001) [Pubmed]
  4. Childhood neuronal ceroid-lipofuscinoses in Argentina. Taratuto, A.L., Saccoliti, M., Sevlever, G., Ruggieri, V., Arroyo, H., Herrero, M., Massaro, M., Fejerman, N. Am. J. Med. Genet. (1995) [Pubmed]
  5. Prosegment of tripeptidyl peptidase I is a potent, slow-binding inhibitor of its cognate enzyme. Golabek, A.A., Dolzhanskaya, N., Walus, M., Wisniewski, K.E., Kida, E. J. Biol. Chem. (2008) [Pubmed]
  6. Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis. Pal, A., Kraetzner, R., Gruene, T., Grapp, M., Schreiber, K., Grønborg, M., Urlaub, H., Becker, S., Asif, A.R., Gärtner, J., Sheldrick, G.M., Steinfeld, R. J. Biol. Chem. (2009) [Pubmed]
  7. Crystal structure and autoactivation pathway of the precursor form of human tripeptidyl-peptidase 1, the enzyme deficient in late infantile ceroid lipofuscinosis. Guhaniyogi, J., Sohar, I., Das, K., Stock, A.M., Lobel, P. J. Biol. Chem. (2009) [Pubmed]
  8. Pheno/genotypic correlations of neuronal ceroid lipofuscinoses. Wisniewski, K.E., Zhong, N., Philippart, M. Neurology (2001) [Pubmed]
  9. Neuronal ceroid lipofuscinoses: research update. Wisniewski, K.E., Kida, E., Connell, F., Zhong, N. Neurol. Sci. (2000) [Pubmed]
  10. Comparison of aminopeptidase, dipeptidyl aminopeptidase and tripeptidyl aminopeptidase activities in brain tissue from normal and Alzheimer's disease cases. Mantle, D., Perry, E.K. J. Neurol. Sci. (1990) [Pubmed]
  11. Shelterin: the protein complex that shapes and safeguards human telomeres. de Lange, T. Genes Dev. (2005) [Pubmed]
  12. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. O'Connor, M.S., Safari, A., Xin, H., Liu, D., Songyang, Z. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  13. Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder. Sleat, D.E., Gin, R.M., Sohar, I., Wisniewski, K., Sklower-Brooks, S., Pullarkat, R.K., Palmer, D.N., Lerner, T.J., Boustany, R.M., Uldall, P., Siakotos, A.N., Donnelly, R.J., Lobel, P. Am. J. Hum. Genet. (1999) [Pubmed]
  14. Biochemical characterization of a lysosomal protease deficient in classical late infantile neuronal ceroid lipofuscinosis (LINCL) and development of an enzyme-based assay for diagnosis and exclusion of LINCL in human specimens and animal models. Sohar, I., Sleat, D.E., Jadot, M., Lobel, P. J. Neurochem. (1999) [Pubmed]
  15. Overexpression in colorectal carcinoma of two lysosomal enzymes, CLN2 and CLN1, involved in neuronal ceroid lipofuscinosis. Tsukamoto, T., Iida, J., Dobashi, Y., Furukawa, T., Konishi, F. Cancer (2006) [Pubmed]
  16. Catalytic residues and substrate specificity of recombinant human tripeptidyl peptidase I (CLN2). Oyama, H., Fujisawa, T., Suzuki, T., Dunn, B.M., Wlodawer, A., Oda, K. J. Biochem. (2005) [Pubmed]
  17. A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis. Awano, T., Katz, M.L., O'brien, D.P., Sohar, I., Lobel, P., Coates, J.R., Khan, S., Johnson, G.C., Giger, U., Johnson, G.S. Mol. Genet. Metab. (2006) [Pubmed]
  18. Loci for classical and a variant late infantile neuronal ceroid lipofuscinosis map to chromosomes 11p15 and 15q21-23. Sharp, J.D., Wheeler, R.B., Lake, B.D., Savukoski, M., Järvelä, I.E., Peltonen, L., Gardiner, R.M., Williams, R.E. Hum. Mol. Genet. (1997) [Pubmed]
  19. Pre- and postnatal enzyme analysis for infantile, late infantile and adult neuronal ceroid lipofuscinosis (CLN1 and CLN2). Van Diggelen, O.P., Keulemans, J.L., Kleijer, W.J., Thobois, S., Tilikete, C., Voznyi, Y.V. Eur. J. Paediatr. Neurol. (2001) [Pubmed]
  20. Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons. Dhar, S., Bitting, R.L., Rylova, S.N., Jansen, P.J., Lockhart, E., Koeberl, D.D., Amalfitano, A., Boustany, R.M. Ann. Neurol. (2002) [Pubmed]
  21. The neuronal ceroid lipofuscinoses: mutations in different proteins result in similar disease. Weimer, J.M., Kriscenski-Perry, E., Elshatory, Y., Pearce, D.A. Neuromolecular Med. (2002) [Pubmed]
  22. Pre- and postnatal diagnosis of patients with CLN1 and CLN2 by assay of palmitoyl-protein thioesterase and tripeptidyl-peptidase I activities. Young, E.P., Worthington, V.C., Jackson, M., Winchester, B.G. Eur. J. Paediatr. Neurol. (2001) [Pubmed]
  23. Neuronal ceroid lipofuscinoses: pathological features of bioptic specimens from 28 patients. Simonati, A., Rizzuto, N. Neurol. Sci. (2000) [Pubmed]
  24. Tripeptidyl-peptidase I in neuronal ceroid lipofuscinoses and other lysosomal storage disorders. Wisniewski, K.E., Kida, E., Walus, M., Wujek, P., Kaczmarski, W., Golabek, A.A. Eur. J. Paediatr. Neurol. (2001) [Pubmed]
  25. Biochemistry of neuronal ceroid lipofuscinoses. Junaid, M.A., Pullarkat, R.K. Adv. Genet. (2001) [Pubmed]
  26. The POT1-TPP1 telomere complex is a telomerase processivity factor. Wang, F., Podell, E.R., Zaug, A.J., Yang, Y., Baciu, P., Cech, T.R., Lei, M. Nature (2007) [Pubmed]
  27. Cellular pathology and pathogenic aspects of neuronal ceroid lipofuscinoses. Kida, E., Golabek, A.A., Wisniewski, K.E. Adv. Genet. (2001) [Pubmed]
  28. Atypical late infantile and juvenile forms of neuronal ceroid lipofuscinosis and their diagnostic difficulties. Wiśniewski, K.E., Zhong, N., Kida, E., Kaczmarski, W., Kaczmarski, A., Connell, F., Brooks, S.S., Brown, W.T. Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences. (1997) [Pubmed]
  29. Lysosomal serine protease CLN2 regulates tumor necrosis factor-alpha-mediated apoptosis in a Bid-dependent manner. Autefage, H., Albinet, V., Garcia, V., Berges, H., Nicolau, M.L., Therville, N., Altié, M.F., Caillaud, C., Levade, T., Andrieu-Abadie, N. J. Biol. Chem. (2009) [Pubmed]
  30. The neuronal ceroid-lipofuscinoses. Goebel, H.H. Seminars in pediatric neurology. (1996) [Pubmed]
  31. Intracranial delivery of CLN2 reduces brain pathology in a mouse model of classical late infantile neuronal ceroid lipofuscinosis. Passini, M.A., Dodge, J.C., Bu, J., Yang, W., Zhao, Q., Sondhi, D., Hackett, N.R., Kaminsky, S.M., Mao, Q., Shihabuddin, L.S., Cheng, S.H., Sleat, D.E., Stewart, G.R., Davidson, B.L., Lobel, P., Crystal, R.G. J. Neurosci. (2006) [Pubmed]
  32. Rapid immunologic diagnosis of classic late infantile neuronal ceroid lipofuscinosis. Kurachi, Y., Oka, A., Mizuguchi, M., Ohkoshi, Y., Sasaki, M., Itoh, M., Hayashi, M., Goto, Y., Takashima, S. Neurology (2000) [Pubmed]
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