Tripeptidyl peptidase I explained

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.^{[1] [2]} TPP1 should not be confused with the TPP1 shelterin protein which protects telomeres and is encoded by the ACD gene.^[3] Mutations in the TPP1 gene leads to late-infantile neuronal ceroid lipofuscinosis.^[4]

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.^[2] 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.^[5] 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.^[6]

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. 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.^[7] 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.^[8] The disease causes childhood onset neurodegeneration resulting in epilepsy, movement disorders and progressive loss of motor and cognitive skills.^{[9] [10]} 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 licenced for use in several countries.^[11]

Further reading

• Mole SE, Mitchison HM, Munroe PB . Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5 . Human Mutation . 14 . 3 . 199–215 . 1999 . 10477428 . 10.1002/(SICI)1098-1004(1999)14:3<199::AID-HUMU3>3.0.CO;2-A . free .
• Dawson G, Cho S . Batten's disease: clues to neuronal protein catabolism in lysosomes . Journal of Neuroscience Research . 60 . 2 . 133–40 . April 2000 . 10740217 . 10.1002/(SICI)1097-4547(20000415)60:2<133::AID-JNR1>3.0.CO;2-3 . 28786470 .
• Hofmann SL, Atashband A, Cho SK, Das AK, Gupta P, Lu JY . Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes (CLN1 and CLN2) . Current Molecular Medicine . 2 . 5 . 423–37 . August 2002 . 12125808 . 10.2174/1566524023362294 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Page AE, Fuller K, Chambers TJ, Warburton MJ . 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 . November 1993 . 8215436 . 10.1006/abbi.1993.1523 .
• Sleat DE, Donnelly RJ, Lackland H, Liu CG, Sohar I, Pullarkat RK, Lobel P . Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis . Science . 277 . 5333 . 1802–5 . September 1997 . 9295267 . 10.1126/science.277.5333.1802 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Rawlings ND, Barrett AJ . 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 . January 1999 . 9989235 . 10.1016/S0167-4838(98)00238-6 .
• Vines DJ, Warburton MJ . Classical late infantile neuronal ceroid lipofuscinosis fibroblasts are deficient in lysosomal tripeptidyl peptidase I . FEBS Letters . 443 . 2 . 131–5 . January 1999 . 9989590 . 10.1016/S0014-5793(98)01683-4 . 41696666 . free .
• 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 . 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 . June 1999 . 10330339 . 1377895 . 10.1086/302427 .
• Junaid MA, Wu G, Pullarkat RK . 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 . January 2000 . 10617131 . 10.1046/j.1471-4159.2000.0740287.x . 25342240 . free .
• Ezaki J, Takeda-Ezaki M, Oda K, Kominami E . 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 . February 2000 . 10679303 . 10.1006/bbrc.2000.2207 .
• Haines JL, Boustany RM, Alroy J, Auger KJ, Shook KS, Terwedow H, Lerner TJ . Chromosomal localization of two genes underlying late-infantile neuronal ceroid lipofuscinosis . Neurogenetics . 1 . 3 . 217–22 . March 1998 . 10737126 . 10.1007/s100480050032 . 23303630 .
• Ezaki J, Takeda-Ezaki M, Kominami E . 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 . September 2000 . 10965052 . 10.1093/oxfordjournals.jbchem.a022781 .
• Lin L, Sohar I, Lackland H, Lobel P . 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 . January 2001 . 11054422 . 10.1074/jbc.M008562200 . free .
• Lam CW, Poon PM, Tong SF, Ko CH . 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 . March 2001 . 11241479 . 10.1002/1096-8628(2001)9999:9999<::AID-AJMG1145>3.0.CO;2-Z .
• Zhong N, Moroziewicz DN, Ju W, Jurkiewicz A, Johnston L, Wisniewski KE, Brown WT . Heterogeneity of late-infantile neuronal ceroid lipofuscinosis . Genetics in Medicine . 2 . 6 . 312–8 . 2001 . 11339651 . 10.1097/00125817-200011000-00002 . free .

External links

• The MEROPS online database for peptidases and their inhibitors: S53.003
• GeneReviews/NCBI/NIH/UW entry on Neuronal Ceroid-Lipofuscinoses

Notes and References

1. Liu CG, Sleat DE, Donnelly RJ, Lobel P . Structural organization and sequence of CLN2, the defective gene in classical late infantile neuronal ceroid lipofuscinosis . Genomics . 50 . 2 . 206–12 . June 1998 . 9653647 . 10.1006/geno.1998.5328 .
2. Web site: Entrez Gene: TPP1 tripeptidyl peptidase I.
3. Web site: ACD ACD, shelterin complex subunit and telomerase recruitment factor [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2017-02-03.
4. Bukina AM, Tsvetkova IV, Semiachkina AN, Il'ina ES . [Tripeptidyl peptidase 1 deficiency in neuronal ceroid lipofuscinosis. A novel mutation] . Voprosy Meditsinskoi Khimii . 48 . 6 . 594–8 . Nov 2002 . 12698559 .
5. Web site: Uniprot: O14773 - TPP1_HUMAN.
6. Pal A, Kraetzner R, Gruene T, Grapp M, Schreiber K, Grønborg M, Urlaub H, Becker S, Asif AR, Gärtner J, Sheldrick GM, Steinfeld R . 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 . February 2009 . 19038966 . 10.1074/jbc.M806947200 . free . 11858/00-001M-0000-0012-D8E3-A . free .
7. Williams . Ruth E. . Mole . Sara E. . 2012-07-10 . New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses . Neurology . en . 79 . 2 . 183–191 . 10.1212/WNL.0b013e31825f0547 . 0028-3878.
8. Gardiner RM . The molecular genetic basis of the neuronal ceroid lipofuscinoses . Neurological Sciences . 21 . 3 Suppl . S15–9 . 2000 . 11073223 . 10.1007/s100720070035 . 9550598 .
9. 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 . en . 69 . 6 . 521–535 . 10.1212/01.wnl.0000267885.47092.40 . 0028-3878.
10. 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 . en . 103 . 3 . 10.1212/WNL.0000000000209615 . 0028-3878. 11314953 .
11. 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 . en . 378 . 20 . 1898–1907 . 10.1056/NEJMoa1712649 . 0028-4793.