Tripeptidyl peptidase I

Tripeptidyl peptidase I
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1R60​, 3EDY​, 3EE6​
Identifiers
Symbols	TPP1 ; CLN2; GIG1; LPIC; SCAR7; TPP-1
External IDs	OMIM: 607998 MGI: 1336194 HomoloGene: 335 GeneCards: TPP1 Gene
EC number	3.4.14.9
Gene ontology Molecular function • endopeptidase activity • serine-type endopeptidase activity • protein binding • peptidase activity • serine-type peptidase activity • tripeptidyl-peptidase activity • peptide binding • metal ion binding Cellular component • mitochondrion • lysosome • melanosome • lysosomal lumen • extracellular exosome Biological process • proteolysis • lipid metabolic process • lysosome organization • nervous system development • central nervous system development • protein catabolic process • epithelial cell differentiation • endoplasmic reticulum unfolded protein response • IRE1-mediated unfolded protein response • peptide catabolic process • cellular protein metabolic process • bone resorption • neuromuscular process controlling balance Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1200	12751
Ensembl	ENSG00000166340	ENSMUSG00000030894
UniProt	O14773	O89023
RefSeq (mRNA)	NM_000391	NM_009906
RefSeq (protein)	NP_000382	NP_034036
Location (UCSC)	Chr 11: 6.61 – 6.62 Mb	Chr 7: 105.74 – 105.75 Mb
PubMed search

Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1 gene.^[1][2]

Gene

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.^[2]

Structure

The human tripeptidyl-peptidase 1 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.^[3]

Function

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).^[4] 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.^[5]

References

1. Liu CG, Sleat DE, Donnelly RJ, Lobel P (Jun 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.
2. "Entrez Gene: TPP1 tripeptidyl peptidase I".
3. "Uniprot: O14773 - TPP1_HUMAN".
4. Getty AL, Pearce DA (Feb 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. PMID 20680390.
5. Gardiner RM (2000). "The molecular genetic basis of the neuronal ceroid lipofuscinoses". Neurological Sciences 21 (3 Suppl): S15–9. PMID 11073223.

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 (Apr 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.
• Hofmann SL, Atashband A, Cho SK, Das AK, Gupta P, Lu JY (Aug 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 (Jan 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 (Nov 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 (Sep 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 (Oct 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 (Jan 1999). "Tripeptidyl-peptidase I is apparently the CLN2 protein absent in classical late-infantile neuronal ceroid lipofuscinosis". Biochimica et Biophysica Acta 1429 (2): 496–500. doi:10.1016/S0167-4838(98)00238-6. PMID 9989235.
• Vines DJ, Warburton MJ (Jan 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.
• 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 (Jun 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 (Jan 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.
• Ezaki J, Takeda-Ezaki M, Oda K, Kominami E (Feb 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 (Mar 1998). "Chromosomal localization of two genes underlying late-infantile neuronal ceroid lipofuscinosis". Neurogenetics 1 (3): 217–22. doi:10.1007/s100480050032. PMID 10737126.
• Ezaki J, Takeda-Ezaki M, Kominami E (Sep 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 (Jan 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 (Mar 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