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3edy, resolution 1.85Å ()
Ligands: , ,
Gene: TPP1, CLN2 (Homo sapiens)
Activity: Tripeptidyl-peptidase I, with EC number
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Crystal Structure of the Precursor Form of Human Tripeptidyl-Peptidase 1

Publication Abstract from PubMed

Late infantile neuronal ceroid lipofuscinosis is a fatal childhood neurological disorder caused by a deficiency in the lysosomal protease tripeptidyl-peptidase 1 (TPP1). TPP1 represents the only known mammalian member of the S53 family of serine proteases, a group characterized by a subtilisin-like fold, a Ser-Glu-Asp catalytic triad, and an acidic pH optimum. TPP1 is synthesized as an inactive proenzyme (pro-TPP1) that is proteolytically processed into the active enzyme after exposure to low pH in vitro or targeting to the lysosome in vivo. In this study, we describe an endoglycosidase H-deglycosylated form of TPP1 containing four Asn-linked N-acetylglucosamines that is indistinguishable from fully glycosylated TPP1 in terms of autocatalytic processing of the proform and enzymatic properties of the mature protease. The crystal structure of deglycosylated pro-TPP1 was determined at 1.85 A resolution. A large 151-residue C-shaped prodomain makes extensive contacts as it wraps around the surface of the catalytic domain with the two domains connected by a 24-residue flexible linker that passes through the substrate-binding groove. The proenzyme structure reveals suboptimal catalytic triad geometry with its propiece linker partially blocking the substrate-binding site, which together serve to prevent premature activation of the protease. Finally, we have identified numerous processing intermediates and propose a structural model that explains the pathway for TPP1 activation in vitro. These data provide new insights into TPP1 function and represent a valuable resource for constructing improved TPP1 variants for treatment of late infantile neuronal ceroid lipofuscinosis.

Crystal Structure and Autoactivation Pathway of the Precursor Form of Human Tripeptidyl-peptidase 1, the Enzyme Deficient in Late Infantile Ceroid Lipofuscinosis., Guhaniyogi J, Sohar I, Das K, Stock AM, Lobel P, J Biol Chem. 2009 Feb 6;284(6):3985-97. Epub 2008 Nov 26. PMID:19038967

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.


[TPP1_HUMAN] Defects in TPP1 are the cause of neuronal ceroid lipofuscinosis type 2 (CLN2) [MIM:204500]. A form of neuronal ceroid lipofuscinosis. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. The lipopigment pattern seen most often in CLN2 consists of curvilinear profiles.[1][2][3][4][5][6][7][8][9][10][11][12][13]


[TPP1_HUMAN] Lysosomal serine protease with tripeptidyl-peptidase I activity. May act as a non-specific lysosomal peptidase which generates tripeptides from the breakdown products produced by lysosomal proteinases. Requires substrates with an unsubstituted N-terminus (By similarity).

About this Structure

3edy is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See Also


  • Guhaniyogi J, Sohar I, Das K, Stock AM, Lobel P. Crystal Structure and Autoactivation Pathway of the Precursor Form of Human Tripeptidyl-peptidase 1, the Enzyme Deficient in Late Infantile Ceroid Lipofuscinosis. J Biol Chem. 2009 Feb 6;284(6):3985-97. Epub 2008 Nov 26. PMID:19038967 doi:M806943200
  1. 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. 1997 Sep 19;277(5333):1802-5. PMID:9295267
  2. 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. Am J Hum Genet. 1999 Jun;64(6):1511-23. PMID:10330339 doi:10.1086/302427
  3. Berry-Kravis E, Sleat DE, Sohar I, Meyer P, Donnelly R, Lobel P. Prenatal testing for late infantile neuronal ceroid lipofuscinosis. Ann Neurol. 2000 Feb;47(2):254-7. PMID:10665500
  4. Zhong N, Moroziewicz DN, Ju W, Jurkiewicz A, Johnston L, Wisniewski KE, Brown WT. Heterogeneity of late-infantile neuronal ceroid lipofuscinosis. Genet Med. 2000 Nov-Dec;2(6):312-8. PMID:11339651
  5. Lam CW, Poon PM, Tong SF, Ko CH. Two novel CLN2 gene mutations in a Chinese patient with classical late-infantile neuronal ceroid lipofuscinosis. Am J Med Genet. 2001 Mar 1;99(2):161-3. PMID:11241479
  6. Mole SE, Zhong NA, Sarpong A, Logan WP, Hofmann S, Yi W, Franken PF, van Diggelen OP, Breuning MH, Moroziewicz D, Ju W, Salonen T, Holmberg V, Jarvela I, Taschner PE. New mutations in the neuronal ceroid lipofuscinosis genes. Eur J Paediatr Neurol. 2001;5 Suppl A:7-10. PMID:11589012
  7. Steinfeld R, Heim P, von Gregory H, Meyer K, Ullrich K, Goebel HH, Kohlschutter A. Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations. Am J Med Genet. 2002 Nov 1;112(4):347-54. PMID:12376936 doi:10.1002/ajmg.10660
  8. Ju W, Zhong R, Moore S, Moroziewicz D, Currie JR, Parfrey P, Brown WT, Zhong N. Identification of novel CLN2 mutations shows Canadian specific NCL2 alleles. J Med Genet. 2002 Nov;39(11):822-5. PMID:12414822
  9. Bukina AM, Tsvetkova IV, Semiachkina AN, Il'ina ES. [Tripeptidyl peptidase 1 deficiency in neuronal ceroid lipofuscinosis. A novel mutation]. Vopr Med Khim. 2002 Nov-Dec;48(6):594-8. PMID:12698559
  10. Tsiakas K, Steinfeld R, Storch S, Ezaki J, Lukacs Z, Kominami E, Kohlschutter A, Ullrich K, Braulke T. Mutation of the glycosylated asparagine residue 286 in human CLN2 protein results in loss of enzymatic activity. Glycobiology. 2004 Apr;14(4):1C-5C. Epub 2004 Jan 21. PMID:14736728 doi:10.1093/glycob/cwh054
  11. Kousi M, Siintola E, Dvorakova L, Vlaskova H, Turnbull J, Topcu M, Yuksel D, Gokben S, Minassian BA, Elleder M, Mole SE, Lehesjoki AE. Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis. Brain. 2009 Mar;132(Pt 3):810-9. doi: 10.1093/brain/awn366. Epub 2009 Feb 5. PMID:19201763 doi:10.1093/brain/awn366
  12. Walus M, Kida E, Golabek AA. Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I. Hum Mutat. 2010 Jun;31(6):710-21. doi: 10.1002/humu.21251. PMID:20340139 doi:10.1002/humu.21251
  13. Kousi M, Lehesjoki AE, Mole SE. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat. 2012 Jan;33(1):42-63. doi: 10.1002/humu.21624. Epub 2011 Nov 16. PMID:21990111 doi:10.1002/humu.21624

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