Tripeptidyl peptidase I

Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1 gene, also known as CLN2.^[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]

TPP1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3EDY, 3EE6
Identifiers
Aliases	TPP1, CLN2, LPIC, SCAR7, TPP-1, GIG1, Tripeptidyl peptidase I, tripeptidyl peptidase 1
External IDs	OMIM: 607998; MGI: 1336194; HomoloGene: 335; GeneCards: TPP1; OMA:TPP1 - orthologs
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11p15.4 Start 6,612,768 bp[1] End 6,619,448 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7 E3|7 55.97 cM Start 105,394,018 bp[2] End 105,401,442 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in retinal pigment epithelium dorsal motor nucleus of vagus nerve inferior olivary nucleus right adrenal cortex germinal epithelium visceral pleura stromal cell of endometrium left adrenal gland spleen parietal pleura Top expressed in choroid plexus of fourth ventricle calvaria stroma of bone marrow tibiofemoral joint retinal pigment epithelium transitional epithelium of urinary bladder decidua right kidney ciliary body right lung More reference expression data BioGPS More reference expression data
Gene ontology Molecular function tripeptidyl-peptidase activity peptide binding endopeptidase activity metal ion binding peptidase activity protein binding serine-type peptidase activity serine-type endopeptidase activity hydrolase activity Cellular component melanosome lysosomal lumen mitochondrion lysosome extracellular exosome Biological process epithelial 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 process Sources:Amigo / QuickGO
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: 105.39 – 105.4 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Gene

The human gene TPP1 encodes a member of the sedolisin family of serine protease enzymes. The human gene has 13 exons and locates at the chromosome band 11p15.^[6] It is also known as CLN2, due to the relation to the disease.

Protein

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.^[10] 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. Bi-allelic mutations of the gene TPP1 have been found to result in one of these disorders, called late-infantile neuronal ceroid lipofuscinosis, also known as CLN type 2 or Jansky–Bielschowsky disease.^[11] Mutations of gene is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome and accumulation of the fluorescent pigments.^[12] The disease causes childhood onset neurodegeneration resulting in epilepsy, movement disorders and progressive loss of motor and cognitive skills.^[13][14] Additionally, it causes retinal degeneration resulting in progressive loss of vision. Enzyme replacement therapy with cerliponase alfa can alter this course of disease, and is licensed for use in several countries.^[15]

References

1. GRCh38: Ensembl release 89: ENSG00000166340 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000030894 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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.
6. "Entrez Gene: TPP1 tripeptidyl peptidase I".
7. "ACD ACD, shelterin complex subunit and telomerase recruitment factor [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-02-03.
8. Bukina AM, Tsvetkova IV, Semiachkina AN, Il'ina ES (Nov 2002). "[Tripeptidyl peptidase 1 deficiency in neuronal ceroid lipofuscinosis. A novel mutation]". Voprosy Meditsinskoi Khimii. 48 (6): 594–8. PMID 12698559.
9. "Uniprot: O14773 - TPP1_HUMAN".
10. Pal 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. hdl:11858/00-001M-0000-0012-D8E3-A. PMID 19038966.
11. Williams, Ruth E.; Mole, Sara E. (2012-07-10). "New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses". Neurology. 79 (2): 183–191. doi:10.1212/WNL.0b013e31825f0547. ISSN 0028-3878. PMID 22778232.
12. 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.
13. Worgall, S.; Kekatpure, M. V.; Heier, L.; Ballon, D.; Dyke, J. P.; Shungu, D.; Mao, X.; Kosofsky, B.; Kaplitt, M. G.; Souweidane, M. M.; Sondhi, D.; Hackett, N. R.; Hollmann, C.; Crystal, R. G. (2007-08-07). "Neurological deterioration in late infantile neuronal ceroid lipofuscinosis". Neurology. 69 (6): 521–535. doi:10.1212/01.wnl.0000267885.47092.40. ISSN 0028-3878. PMID 17679671.
14. Spaull, Robert; Soo, Audrey K.; Batzios, Spyros; Footitt, Emma; Whiteley, Rebecca; Mink, Jonathan W.; Carr, Lucinda; Gissen, Paul; Kurian, Manju A. (2024-08-13). "Evolution of Movement Disorders in Patients With CLN2-Batten Disease Treated With Enzyme Replacement Therapy". Neurology. 103 (3): e209615. doi:10.1212/WNL.0000000000209615. ISSN 0028-3878. PMC 11314953. PMID 38976822.
15. Schulz, Angela; Ajayi, Temitayo; Specchio, Nicola; de Los Reyes, Emily; Gissen, Paul; Ballon, Douglas; Dyke, Jonathan P.; Cahan, Heather; Slasor, Peter; Jacoby, David; Kohlschütter, Alfried (2018-05-17). "Study of Intraventricular Cerliponase Alfa for CLN2 Disease". New England Journal of Medicine. 378 (20): 1898–1907. doi:10.1056/NEJMoa1712649. ISSN 0028-4793. PMID 29688815.

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. 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<::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.