Трипептидил пептидаза i

TPP1
Доступные структуры PDB Поиск ортолога: PDBE RCSB показывать Список кодов идентификаторов PDB 3EDY, 3EE6
Идентификаторы
Псевдонимы	TPP1 , CLN2, LPIC, SCAR7, TPP-1, GIG1, трипептидилпептидаза I, трипептидилпептидаза 1
Внешние идентификаторы	Омим : 607998 ; MGI : 1336194 ; Гомологен : 335 ; GeneCards : TPP1 ; OMA : TPP1 - ортологи
показывать Местоположение гена ( человек ) Chr. Chromosome 11 (human) Band 11p15.4 Start 6,612,768 bp End 6,619,448 bp
showGene location (Mouse) Chr. Chromosome 7 (mouse) Band 7 E3|7 55.97 cM Start 105,394,018 bp End 105,401,442 bp
showRNA 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
showGene 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
hideOrthologs 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
Wikidata
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Триптидилпептидаза 1 , также известная как лизосомальная пепстатин, нечувствительная протеаза , является ферментом , который у людей кодируется TPP1 геном , также известным как CLN2 . TPP1 не следует путать с белком Shelterin TPP1, который защищает теломер и кодируется геном ACD . Мутации в гене TPP1 приводят к позднему нефантильному нейрональному цероидному липофусцинозу .

Структура

Ген

Человеческий ген TPP1 кодирует члена седолизинов семейства сериновой протеазы . Человеческий ген имеет 13 экзонов и расположена в диапазоне хромосом 11p15. Он также известен как CLN2 из -за отношения к заболеванию.

Белок

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. 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.

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. 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. The disease causes childhood onset neurodegeneration resulting in epilepsy, movement disorders and progressive loss of motor and cognitive skills. 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.

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, Wisniewki KE, Brown WT (2001). «Гетерогенность позднего нефантильного нейронального цероидного липофусциноза» . Генетика в медицине . 2 (6): 312–8. doi : 10.1097/00125817-200011000-00002 . PMID   11339651 .

Внешние ссылки

• Онлайн -база данных Merops : для пептидаз и их ингибиторов S53.003
• Genereviews/ncbi/nih/uw inpity на нейрональных Ceroid-lipofuscinoses
• Обзор всей структурной информации, доступной в PDB для Uniprot : O14773 (триппептидилпептидаза 1) в PDBE-KB .