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3ee6

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Revision as of 22:23, 5 August 2016

Crystal Structure Analysis of Tripeptidyl peptidase -I

Structural highlights

3ee6 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Gene:	CLN2 (HUMAN)
Activity:	Tripeptidyl-peptidase I, with EC number 3.4.14.9
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[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]

Function

[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).

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Late infantile neuronal ceroid lipofuscinosis, a fatal neurodegenerative disease of childhood, is caused by mutations in the TPP1 gene that encodes tripeptidyl-peptidase I. We show that purified TPP1 requires at least partial glycosylation for in vitro autoprocessing and proteolytic activity. We crystallized the fully glycosylated TPP1 precursor under conditions that implied partial autocatalytic cleavage between the prosegment and the catalytic domain. X-ray crystallographic analysis at 2.35 angstroms resolution reveals a globular structure with a subtilisin-like fold, a Ser475-Glu272-Asp360 catalytic triad, and an octahedrally coordinated Ca2+-binding site that are characteristic features of the S53 sedolisin family of peptidases. In contrast to other S53 peptidases, the TPP1 structure revealed steric constraints on the P4 substrate pocket explaining 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. 28 disease-causing missense mutations are analyzed in the light of the TPP1 structure providing insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis.

Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis.,Pal A, Kraetzner R, Gruene T, Grapp M, Schreiber K, Gronborg M, Urlaub H, Becker S, Asif AR, Gartner J, Sheldrick GM, Steinfeld R J Biol Chem. 2009 Feb 6;284(6):3976-84. Epub 2008 Nov 26. PMID:19038966^[14]

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

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ Pal A, Kraetzner R, Gruene T, Grapp M, Schreiber K, Gronborg M, Urlaub H, Becker S, Asif AR, Gartner J, Sheldrick GM, Steinfeld R. Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis. J Biol Chem. 2009 Feb 6;284(6):3976-84. Epub 2008 Nov 26. PMID:19038966 doi:10.1074/jbc.M806947200

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3ee6"

@@ Line 1: / Line 1: @@
 ==Crystal Structure Analysis of Tripeptidyl peptidase -I==
 <StructureSection load='3ee6' size='340' side='right' caption='[[3ee6]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3ee6]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EE6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3EE6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3ee6]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EE6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3EE6 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CLN2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CLN2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Tripeptidyl-peptidase_I Tripeptidyl-peptidase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.14.9 3.4.14.9] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ee6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ee6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ee6 RCSB], [http://www.ebi.ac.uk/pdbsum/3ee6 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ee6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ee6 OCA], [http://pdbe.org/3ee6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ee6 RCSB], [http://www.ebi.ac.uk/pdbsum/3ee6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ee6 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3ee6 ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 30: / Line 31: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3ee6" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 38: / Line 40: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Tripeptidyl-peptidase I]]
 [[Category: Asif, A R]]

3ee6

From Proteopedia

Revision as of 22:23, 5 August 2016

Crystal Structure Analysis of Tripeptidyl peptidase -I

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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