Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1gene.[5][6] TPP1 should not be confused with the TPP1 shelterin protein which protects telomeres and is encoded by the ACD gene.[7]Mutations in the TPP1 gene leads to late infantile neuronal ceroid lipofuscinosis.[8]
The human TPP1 is 61kDa in size and composed of 563 amino acids. An isoform of 34.5kDa and 320 amino acids is generated by alternative splicing and a peptide fragment of 1-243 amino acid is missing.[9] TPP1 contains a globular structure with a subtilisin-like fold, a Ser475-Glu272-Asp360 catalytic triad. It also contains an octahedrally coordinated Ca2+-binding site that are characteristic features of the S53 sedolisin family of peptidases. Unlike other S53 peptidases, it has steric constraints on the P4 substrate pocket, which might contribute to its preferential cleavage of tripeptides from the unsubstituted N-terminus of proteins. Two alternative conformations of the catalytic Asp276 are associated with the activation status of TPP1.[10]
Function
High expression of TPP1 is found in bone marrow, placenta, lung, pineal and lymphocytes. 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 autoproteolyzed upon acidification.
Clinical significance
The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders with pathological phenotypes that auto fluorescent lipopigments present in neurons and other cell types. Over the past two decades, accumulating evidences indicates that NCLs are caused by mutations in eight different genes, including genes encoding several soluble proteins (cathepsin D, PPT1, and TPP1).[11] Mutations of gene TPP1 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.[12] Mutations in the TPP1 gene lead to late infantile neuronal ceroid lipofuscinosis, a fatal neurodegenerative disease of childhood.[10] It has been demonstrated that a single injection of intravitreal implantation of autologous bone marrow derived stem cells transduced with a TPP1 expression construct at an early stage in the disease progression could substantially inhibit the development of disease-related retinal function deficits and structural changes. This result implies that ex vivo gene therapy using autologous stem cells may be an effective means of achieving sustained delivery of therapeutic compounds to tissues such as the retina for which systemic administration would be ineffective.[13]
References
^ abcGRCh38: Ensembl release 89: ENSG00000166340 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000030894 - Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Liu CG, Sleat DE, Donnelly RJ, Lobel P (June 1998). "Structural organization and sequence of CLN2, the defective gene in classical late infantile neuronal ceroid lipofuscinosis". Genomics. 50 (2): 206–12. doi:10.1006/geno.1998.5328. PMID 9653647.
^ abPal A, Kraetzner R, Gruene T, Grapp M, Schreiber K, Grønborg M, Urlaub H, Becker S, Asif AR, Gärtner J, Sheldrick GM, Steinfeld R (February 2009). "Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis". The Journal of Biological Chemistry. 284 (6): 3976–84. doi:10.1074/jbc.M806947200. PMID 19038966.
^Getty AL, Pearce DA (February 2011). "Interactions of the proteins of neuronal ceroid lipofuscinosis: clues to function". Cellular and Molecular Life Sciences. 68 (3): 453–74. doi:10.1007/s00018-010-0468-6. PMC4120758. PMID 20680390.
^Gardiner RM (2000). "The molecular genetic basis of the neuronal ceroid lipofuscinoses". Neurological Sciences. 21 (3 Suppl): S15–9. doi:10.1007/s100720070035. PMID 11073223. S2CID 9550598.
^Tracy CJ, Whiting RE, Pearce JW, Williamson BG, Vansteenkiste DP, Gillespie LE, Castaner LJ, Bryan JN, Coates JR, Jensen CA, Katz ML (September 2016). "Intravitreal implantation of TPP1-transduced stem cells delays retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis". Experimental Eye Research. 152: 77–87. doi:10.1016/j.exer.2016.09.003. PMID 27637672.
Further reading
Mole SE, Mitchison HM, Munroe PB (1999). "Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5". Human Mutation. 14 (3): 199–215. doi:10.1002/(SICI)1098-1004(1999)14:3<199::AID-HUMU3>3.0.CO;2-A. PMID 10477428.
Dawson G, Cho S (April 2000). "Batten's disease: clues to neuronal protein catabolism in lysosomes". Journal of Neuroscience Research. 60 (2): 133–40. doi:10.1002/(SICI)1097-4547(20000415)60:2<133::AID-JNR1>3.0.CO;2-3. PMID 10740217. S2CID 28786470.
Hofmann SL, Atashband A, Cho SK, Das AK, Gupta P, Lu JY (August 2002). "Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes (CLN1 and CLN2)". Current Molecular Medicine. 2 (5): 423–37. doi:10.2174/1566524023362294. PMID 12125808.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
Page AE, Fuller K, Chambers TJ, Warburton MJ (November 1993). "Purification and characterization of a tripeptidyl peptidase I from human osteoclastomas: evidence for its role in bone resorption". Archives of Biochemistry and Biophysics. 306 (2): 354–9. doi:10.1006/abbi.1993.1523. PMID 8215436.
Sleat DE, Donnelly RJ, Lackland H, Liu CG, Sohar I, Pullarkat RK, Lobel P (September 1997). "Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis". Science. 277 (5333): 1802–5. doi:10.1126/science.277.5333.1802. PMID 9295267.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
Rawlings ND, Barrett AJ (January 1999). "Tripeptidyl-peptidase I is apparently the CLN2 protein absent in classical late-infantile neuronal ceroid lipofuscinosis". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1429 (2): 496–500. doi:10.1016/S0167-4838(98)00238-6. PMID 9989235.
Vines DJ, Warburton MJ (January 1999). "Classical late infantile neuronal ceroid lipofuscinosis fibroblasts are deficient in lysosomal tripeptidyl peptidase I". FEBS Letters. 443 (2): 131–5. doi:10.1016/S0014-5793(98)01683-4. PMID 9989590. S2CID 41696666.
Sleat DE, Gin RM, Sohar I, Wisniewski K, Sklower-Brooks S, Pullarkat RK, Palmer DN, Lerner TJ, Boustany RM, Uldall P, Siakotos AN, Donnelly RJ, Lobel P (June 1999). "Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder". American Journal of Human Genetics. 64 (6): 1511–23. doi:10.1086/302427. PMC1377895. PMID 10330339.
Junaid MA, Wu G, Pullarkat RK (January 2000). "Purification and characterization of bovine brain lysosomal pepstatin-insensitive proteinase, the gene product deficient in the human late-infantile neuronal ceroid lipofuscinosis". Journal of Neurochemistry. 74 (1): 287–94. doi:10.1046/j.1471-4159.2000.0740287.x. PMID 10617131. S2CID 25342240.
Ezaki J, Takeda-Ezaki M, Oda K, Kominami E (February 2000). "Characterization of endopeptidase activity of tripeptidyl peptidase-I/CLN2 protein which is deficient in classical late infantile neuronal ceroid lipofuscinosis". Biochemical and Biophysical Research Communications. 268 (3): 904–8. doi:10.1006/bbrc.2000.2207. PMID 10679303.
Ezaki J, Takeda-Ezaki M, Kominami E (September 2000). "Tripeptidyl peptidase I, the late infantile neuronal ceroid lipofuscinosis gene product, initiates the lysosomal degradation of subunit c of ATP synthase". Journal of Biochemistry. 128 (3): 509–16. doi:10.1093/oxfordjournals.jbchem.a022781. PMID 10965052.
Lin L, Sohar I, Lackland H, Lobel P (January 2001). "The human CLN2 protein/tripeptidyl-peptidase I is a serine protease that autoactivates at acidic pH". The Journal of Biological Chemistry. 276 (3): 2249–55. doi:10.1074/jbc.M008562200. PMID 11054422.
Lam CW, Poon PM, Tong SF, Ko CH (March 2001). "Two novel CLN2 gene mutations in a Chinese patient with classical late-infantile neuronal ceroid lipofuscinosis". American Journal of Medical Genetics. 99 (2): 161–3. doi:10.1002/1096-8628(2001)9999:9999<::AID-AJMG1145>3.0.CO;2-Z. PMID 11241479.
Zhong N, Moroziewicz DN, Ju W, Jurkiewicz A, Johnston L, Wisniewski KE, Brown WT (2001). "Heterogeneity of late-infantile neuronal ceroid lipofuscinosis". Genetics in Medicine. 2 (6): 312–8. doi:10.1097/00125817-200011000-00002. PMID 11339651.
External links
The MEROPS online database for peptidases and their inhibitors: S53.003
GeneReviews/NCBI/NIH/UW entry on Neuronal Ceroid-Lipofuscinoses
Overview of all the structural information available in the PDB for UniProt: O14773 (Tripeptidyl-peptidase 1) at the PDBe-KB.
tripeptidyl, peptidase, tripeptidyl, peptidase, also, known, lysosomal, pepstatin, insensitive, protease, enzyme, that, humans, encoded, tpp1, gene, tpp1, should, confused, with, tpp1, shelterin, protein, which, protects, telomeres, encoded, gene, mutations, t. Tripeptidyl peptidase 1 also known as Lysosomal pepstatin insensitive protease is an enzyme that in humans is encoded by the TPP1 gene 5 6 TPP1 should not be confused with the TPP1 shelterin protein which protects telomeres and is encoded by the ACD gene 7 Mutations in the TPP1 gene leads to late infantile neuronal ceroid lipofuscinosis 8 TPP1Available structuresPDBOrtholog search PDBe RCSBList of PDB id codes3EDY 3EE6IdentifiersAliasesTPP1 CLN2 LPIC SCAR7 TPP 1 GIG1 Tripeptidyl peptidase I tripeptidyl peptidase 1External IDsOMIM 607998 MGI 1336194 HomoloGene 335 GeneCards TPP1Gene location Human Chr Chromosome 11 human 1 Band11p15 4Start6 612 768 bp 1 End6 619 448 bp 1 Gene location Mouse Chr Chromosome 7 mouse 2 Band7 E3 7 55 97 cMStart105 394 018 bp 2 End105 401 442 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inretinal pigment epitheliuminferior olivary nucleusgerminal epitheliumvisceral pleurastromal cell of endometriumLeft adrenal glandspleenparietal pleuramonocytecancellous boneTop expressed incalvariaretinal pigment epitheliumciliary bodyright lungproximal tubulesternocleidomastoid musclekidneyankleright lung lobetriceps brachii muscleMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functiontripeptidyl peptidase activity peptide binding endopeptidase activity metal ion binding peptidase activity protein binding serine type peptidase activity serine type endopeptidase activity hydrolase activityCellular componentmelanosome lysosomal lumen mitochondrion lysosome extracellular exosomeBiological processepithelial cell differentiation neuromuscular process controlling balance lipid metabolism bone resorption nervous system development proteolysis central nervous system development IRE1 mediated unfolded protein response protein catabolic process lysosome organization peptide catabolic processSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez120012751EnsemblENSG00000166340ENSMUSG00000030894UniProtO14773O89023RefSeq mRNA NM 000391NM 009906RefSeq protein NP 000382NP 034036Location UCSC Chr 11 6 61 6 62 MbChr 7 105 39 105 4 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Structure 1 1 Gene 1 2 Protein 2 Function 3 Clinical significance 4 References 5 Further reading 6 External linksStructure EditGene Edit The human gene TPP1 encodes a member of the sedolisin family of serine proteases The human gene has 13 exons and locates at the chromosome band 11p15 6 Protein Edit The human TPP1 is 61kDa in size and composed of 563 amino acids An isoform of 34 5kDa and 320 amino acids is generated by alternative splicing and a peptide fragment of 1 243 amino acid is missing 9 TPP1 contains a globular structure with a subtilisin like fold a Ser475 Glu272 Asp360 catalytic triad It also contains an octahedrally coordinated Ca2 binding site that are characteristic features of the S53 sedolisin family of peptidases Unlike other S53 peptidases it has steric constraints on the P4 substrate pocket which might contribute to its preferential cleavage of tripeptides from the unsubstituted N terminus of proteins Two alternative conformations of the catalytic Asp276 are associated with the activation status of TPP1 10 Function EditHigh expression of TPP1 is found in bone marrow placenta lung pineal and lymphocytes 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 autoproteolyzed upon acidification Clinical significance EditThe neuronal ceroid lipofuscinoses NCLs are a group of inherited neurodegenerative disorders with pathological phenotypes that auto fluorescent lipopigments present in neurons and other cell types Over the past two decades accumulating evidences indicates that NCLs are caused by mutations in eight different genes including genes encoding several soluble proteins cathepsin D PPT1 and TPP1 11 Mutations of gene TPP1 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 12 Mutations in the TPP1 gene lead to late infantile neuronal ceroid lipofuscinosis a fatal neurodegenerative disease of childhood 10 It has been demonstrated that a single injection of intravitreal implantation of autologous bone marrow derived stem cells transduced with a TPP1 expression construct at an early stage in the disease progression could substantially inhibit the development of disease related retinal function deficits and structural changes This result implies that ex vivo gene therapy using autologous stem cells may be an effective means of achieving sustained delivery of therapeutic compounds to tissues such as the retina for which systemic administration would be ineffective 13 References Edit a b c GRCh38 Ensembl release 89 ENSG00000166340 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000030894 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Liu CG Sleat DE Donnelly RJ Lobel P June 1998 Structural organization and sequence of CLN2 the defective gene in classical late infantile neuronal ceroid lipofuscinosis Genomics 50 2 206 12 doi 10 1006 geno 1998 5328 PMID 9653647 a b Entrez Gene TPP1 tripeptidyl peptidase I ACD ACD shelterin complex subunit and telomerase recruitment factor Homo sapiens human Gene NCBI www ncbi nlm nih gov Retrieved 2017 02 03 Bukina AM Tsvetkova IV Semiachkina AN Il ina ES Nov 2002 Tripeptidyl peptidase 1 deficiency in neuronal ceroid lipofuscinosis A novel mutation Voprosy Medit s inskoĭ Khimii 48 6 594 8 PMID 12698559 Uniprot O14773 TPP1 HUMAN a b Pal A Kraetzner R Gruene T Grapp M Schreiber K Gronborg M Urlaub H Becker S Asif AR Gartner J Sheldrick GM Steinfeld R February 2009 Structure of tripeptidyl peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis The Journal of Biological Chemistry 284 6 3976 84 doi 10 1074 jbc M806947200 PMID 19038966 Getty AL Pearce DA February 2011 Interactions of the proteins of neuronal ceroid lipofuscinosis clues to function Cellular and Molecular Life Sciences 68 3 453 74 doi 10 1007 s00018 010 0468 6 PMC 4120758 PMID 20680390 Gardiner RM 2000 The molecular genetic basis of the neuronal ceroid lipofuscinoses Neurological Sciences 21 3 Suppl S15 9 doi 10 1007 s100720070035 PMID 11073223 S2CID 9550598 Tracy CJ Whiting RE Pearce JW Williamson BG Vansteenkiste DP Gillespie LE Castaner LJ Bryan JN Coates JR Jensen CA Katz ML September 2016 Intravitreal implantation of TPP1 transduced stem cells delays retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis Experimental Eye Research 152 77 87 doi 10 1016 j exer 2016 09 003 PMID 27637672 Further reading EditMole SE Mitchison HM Munroe PB 1999 Molecular basis of the neuronal ceroid lipofuscinoses mutations in CLN1 CLN2 CLN3 and CLN5 Human Mutation 14 3 199 215 doi 10 1002 SICI 1098 1004 1999 14 3 lt 199 AID HUMU3 gt 3 0 CO 2 A PMID 10477428 Dawson G Cho S April 2000 Batten s disease clues to neuronal protein catabolism in lysosomes Journal of Neuroscience Research 60 2 133 40 doi 10 1002 SICI 1097 4547 20000415 60 2 lt 133 AID JNR1 gt 3 0 CO 2 3 PMID 10740217 S2CID 28786470 Hofmann SL Atashband A Cho SK Das AK Gupta P Lu JY August 2002 Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes CLN1 and CLN2 Current Molecular Medicine 2 5 423 37 doi 10 2174 1566524023362294 PMID 12125808 Maruyama K Sugano S January 1994 Oligo capping a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides Gene 138 1 2 171 4 doi 10 1016 0378 1119 94 90802 8 PMID 8125298 Page AE Fuller K Chambers TJ Warburton MJ November 1993 Purification and characterization of a tripeptidyl peptidase I from human osteoclastomas evidence for its role in bone resorption Archives of Biochemistry and Biophysics 306 2 354 9 doi 10 1006 abbi 1993 1523 PMID 8215436 Sleat DE Donnelly RJ Lackland H Liu CG Sohar I Pullarkat RK Lobel P September 1997 Association of mutations in a lysosomal protein with classical late infantile neuronal ceroid lipofuscinosis Science 277 5333 1802 5 doi 10 1126 science 277 5333 1802 PMID 9295267 Suzuki Y Yoshitomo Nakagawa K Maruyama K Suyama A Sugano S October 1997 Construction and characterization of a full length enriched and a 5 end enriched cDNA library Gene 200 1 2 149 56 doi 10 1016 S0378 1119 97 00411 3 PMID 9373149 Rawlings ND Barrett AJ January 1999 Tripeptidyl peptidase I is apparently the CLN2 protein absent in classical late infantile neuronal ceroid lipofuscinosis Biochimica et Biophysica Acta BBA Protein Structure and Molecular Enzymology 1429 2 496 500 doi 10 1016 S0167 4838 98 00238 6 PMID 9989235 Vines DJ Warburton MJ January 1999 Classical late infantile neuronal ceroid lipofuscinosis fibroblasts are deficient in lysosomal tripeptidyl peptidase I FEBS Letters 443 2 131 5 doi 10 1016 S0014 5793 98 01683 4 PMID 9989590 S2CID 41696666 Sleat DE Gin RM Sohar I Wisniewski K Sklower Brooks S Pullarkat RK Palmer DN Lerner TJ Boustany RM Uldall P Siakotos AN Donnelly RJ Lobel P June 1999 Mutational analysis of the defective protease in classic late infantile neuronal ceroid lipofuscinosis a neurodegenerative lysosomal storage disorder American Journal of Human Genetics 64 6 1511 23 doi 10 1086 302427 PMC 1377895 PMID 10330339 Junaid MA Wu G Pullarkat RK January 2000 Purification and characterization of bovine brain lysosomal pepstatin insensitive proteinase the gene product deficient in the human late infantile neuronal ceroid lipofuscinosis Journal of Neurochemistry 74 1 287 94 doi 10 1046 j 1471 4159 2000 0740287 x PMID 10617131 S2CID 25342240 Ezaki J Takeda Ezaki M Oda K Kominami E February 2000 Characterization of endopeptidase activity of tripeptidyl peptidase I CLN2 protein which is deficient in classical late infantile neuronal ceroid lipofuscinosis Biochemical and Biophysical Research Communications 268 3 904 8 doi 10 1006 bbrc 2000 2207 PMID 10679303 Haines JL Boustany RM Alroy J Auger KJ Shook KS Terwedow H Lerner TJ March 1998 Chromosomal localization of two genes underlying late infantile neuronal ceroid lipofuscinosis Neurogenetics 1 3 217 22 doi 10 1007 s100480050032 PMID 10737126 S2CID 23303630 Ezaki J Takeda Ezaki M Kominami E September 2000 Tripeptidyl peptidase I the late infantile neuronal ceroid lipofuscinosis gene product initiates the lysosomal degradation of subunit c of ATP synthase Journal of Biochemistry 128 3 509 16 doi 10 1093 oxfordjournals jbchem a022781 PMID 10965052 Lin L Sohar I Lackland H Lobel P January 2001 The human CLN2 protein tripeptidyl peptidase I is a serine protease that autoactivates at acidic pH The Journal of Biological Chemistry 276 3 2249 55 doi 10 1074 jbc M008562200 PMID 11054422 Lam CW Poon PM Tong SF Ko CH March 2001 Two novel CLN2 gene mutations in a Chinese patient with classical late infantile neuronal ceroid lipofuscinosis American Journal of Medical Genetics 99 2 161 3 doi 10 1002 1096 8628 2001 9999 9999 lt AID AJMG1145 gt 3 0 CO 2 Z PMID 11241479 Zhong N Moroziewicz DN Ju W Jurkiewicz A Johnston L Wisniewski KE Brown WT 2001 Heterogeneity of late infantile neuronal ceroid lipofuscinosis Genetics in Medicine 2 6 312 8 doi 10 1097 00125817 200011000 00002 PMID 11339651 External links EditThe MEROPS online database for peptidases and their inhibitors S53 003 GeneReviews NCBI NIH UW entry on Neuronal Ceroid Lipofuscinoses Overview of all the structural information available in the PDB for UniProt O14773 Tripeptidyl peptidase 1 at the PDBe KB Portal Biology Retrieved from https en wikipedia org w index php title Tripeptidyl peptidase I amp oldid 1142721178, wikipedia, wiki, book, books, library,
