3edy

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{{STRUCTURE_3edy| PDB=3edy | SCENE= }}
 
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===Crystal Structure of the Precursor Form of Human Tripeptidyl-Peptidase 1===
 
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{{ABSTRACT_PUBMED_19038967}}
 
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==Disease==
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==Crystal Structure of the Precursor Form of Human Tripeptidyl-Peptidase 1==
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[[http://www.uniprot.org/uniprot/TPP1_HUMAN TPP1_HUMAN]] Defects in TPP1 are the cause of neuronal ceroid lipofuscinosis type 2 (CLN2) [MIM:[http://omim.org/entry/204500 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.<ref>PMID:9295267</ref><ref>PMID:10330339</ref><ref>PMID:10665500</ref><ref>PMID:11339651</ref><ref>PMID:11241479</ref><ref>PMID:11589012</ref><ref>PMID:12376936</ref><ref>PMID:12414822</ref><ref>PMID:12698559</ref><ref>PMID:14736728</ref><ref>PMID:19201763</ref><ref>PMID:20340139</ref><ref>PMID:21990111</ref>
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<StructureSection load='3edy' size='340' side='right'caption='[[3edy]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3edy]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EDY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3EDY FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3edy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3edy OCA], [https://pdbe.org/3edy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3edy RCSB], [https://www.ebi.ac.uk/pdbsum/3edy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3edy ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/TPP1_HUMAN TPP1_HUMAN] Defects in TPP1 are the cause of neuronal ceroid lipofuscinosis type 2 (CLN2) [MIM:[https://omim.org/entry/204500 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.<ref>PMID:9295267</ref> <ref>PMID:10330339</ref> <ref>PMID:10665500</ref> <ref>PMID:11339651</ref> <ref>PMID:11241479</ref> <ref>PMID:11589012</ref> <ref>PMID:12376936</ref> <ref>PMID:12414822</ref> <ref>PMID:12698559</ref> <ref>PMID:14736728</ref> <ref>PMID:19201763</ref> <ref>PMID:20340139</ref> <ref>PMID:21990111</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/TPP1_HUMAN 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).
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ed/3edy_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=3edy ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==Function==
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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<ref>PMID:19038967</ref>
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[[http://www.uniprot.org/uniprot/TPP1_HUMAN 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).
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3edy]] is a 1 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=3EDY OCA].
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</div>
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<div class="pdbe-citations 3edy" style="background-color:#fffaf0;"></div>
==See Also==
==See Also==
*[[Tripeptidyl peptidase|Tripeptidyl peptidase]]
*[[Tripeptidyl peptidase|Tripeptidyl peptidase]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:019038967</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Tripeptidyl-peptidase I]]
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[[Category: Large Structures]]
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[[Category: Das, K.]]
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[[Category: Das K]]
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[[Category: Guhaniyogi, J.]]
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[[Category: Guhaniyogi J]]
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[[Category: Lobel, P.]]
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[[Category: Lobel P]]
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[[Category: Sohar, I.]]
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[[Category: Sohar I]]
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[[Category: Stock, A M.]]
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[[Category: Stock AM]]
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[[Category: Batten disease]]
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[[Category: Catalytic triad]]
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[[Category: Cln2]]
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[[Category: Disease mutation]]
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[[Category: Endopeptidase]]
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[[Category: Epilepsy]]
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[[Category: Exopeptidase]]
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[[Category: Glycoprotein]]
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[[Category: Hydrolase]]
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[[Category: Lincl]]
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[[Category: Lysosome]]
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[[Category: Neuronal ceroid lipofuscinosis]]
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[[Category: Oxyanion hole]]
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[[Category: Prodomain]]
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[[Category: Protease]]
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[[Category: S53 family]]
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[[Category: Sedolisin]]
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[[Category: Serine protease]]
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[[Category: Tpp1]]
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[[Category: Zymogen]]
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Current revision

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

PDB ID 3edy

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