Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1gene.[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]
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. 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).[7] 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.[8] Mutations in the TPP1 gene lead to late infantile neuronal ceroid lipofuscinosis, a fatal neurodegenerative disease of childhood.[6] 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.[9]
References
↑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. PMID9653647.
↑ 6.06.1Pal 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. PMID19038966.
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. PMID12125808.
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. PMID8125298.
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. PMID8215436.
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. PMID9295267.
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. PMID9373149.
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. 1429 (2): 496–500. doi:10.1016/S0167-4838(98)00238-6. PMID9989235.
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. PMID9989590.
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. Bibcode:2006JNeur..26.9606G. doi:10.1046/j.1471-4159.2000.0740287.x. PMID10617131.
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. PMID10679303.
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. PMID10965052.
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. PMID11054422.
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. PMID11339651.
External links
The MEROPS online database for peptidases and their inhibitors: S53.003