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| | ==Human mesotrypsin complexed with amyloid precursor protein inhibitor variant (APPIR15K)== | | ==Human mesotrypsin complexed with amyloid precursor protein inhibitor variant (APPIR15K)== |
| - | <StructureSection load='3l3t' size='340' side='right' caption='[[3l3t]], [[Resolution|resolution]] 2.38Å' scene=''> | + | <StructureSection load='3l3t' size='340' side='right'caption='[[3l3t]], [[Resolution|resolution]] 2.38Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3l3t]] is a 8 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=3L3T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3L3T FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3l3t]] is a 8 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=3L3T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3L3T 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=FMT:FORMIC+ACID'>FMT</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.378Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r9p|2r9p]], [[1zjd|1zjd]]</td></tr>
| + | <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=FMT:FORMIC+ACID'>FMT</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PRSS3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), APP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3l3t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3l3t OCA], [https://pdbe.org/3l3t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3l3t RCSB], [https://www.ebi.ac.uk/pdbsum/3l3t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3l3t ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Trypsin Trypsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.4 3.4.21.4] </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=3l3t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3l3t OCA], [http://pdbe.org/3l3t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3l3t RCSB], [http://www.ebi.ac.uk/pdbsum/3l3t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3l3t ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/TRY3_HUMAN TRY3_HUMAN] Digestive protease specialized for the degradation of trypsin inhibitors. In the ileum, may be involved in defensin processing, including DEFA5.<ref>PMID:12021776</ref> <ref>PMID:14507909</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | <jmolCheckbox> | | <jmolCheckbox> |
| | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/l3/3l3t_consurf.spt"</scriptWhenChecked> | | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/l3/3l3t_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | ==See Also== | | ==See Also== |
| - | *[[Amyloid precursor protein|Amyloid precursor protein]] | + | *[[Amyloid precursor protein 3D structures|Amyloid precursor protein 3D structures]] |
| - | *[[Trypsin|Trypsin]] | + | *[[Trypsin 3D structures|Trypsin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Trypsin]] | + | [[Category: Large Structures]] |
| - | [[Category: Radisky, E S]] | + | [[Category: Radisky ES]] |
| - | [[Category: Salameh, M A]] | + | [[Category: Salameh MA]] |
| - | [[Category: Soares, A S]] | + | [[Category: Soares AS]] |
| - | [[Category: Alzheimer's amyloid precursor protein inhibitor]]
| + | |
| - | [[Category: Appi]]
| + | |
| - | [[Category: Appi-r15k]]
| + | |
| - | [[Category: Canonical inhibitor]]
| + | |
| - | [[Category: Human mesotrypsin]]
| + | |
| - | [[Category: Hydrolase-cell adhesion complex]]
| + | |
| Structural highlights
Function
TRY3_HUMAN Digestive protease specialized for the degradation of trypsin inhibitors. In the ileum, may be involved in defensin processing, including DEFA5.[1] [2]
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
An important functional property of protein protease inhibitors is their stability to proteolysis. Mesotrypsin is a human trypsin that has been implicated in the proteolytic inactivation of several protein protease inhibitors. We have found that bovine pancreatic trypsin inhibitor (BPTI), a Kunitz protease inhibitor, inhibits mesotrypsin very weakly and is slowly proteolyzed, whereas, despite close sequence and structural homology, the Kunitz protease inhibitor domain of the amyloid precursor protein (APPI) binds to mesotrypsin 100 times more tightly and is cleaved 300 times more rapidly. To define features responsible for these differences, we have assessed the binding and cleavage by mesotrypsin of APPI and BPTI reciprocally mutated at two nonidentical residues that make direct contact with the enzyme. We find that Arg at P(1) (versus Lys) favors both tighter binding and more rapid cleavage, whereas Met (versus Arg) at P'(2) favors tighter binding but has minimal effect on cleavage. Surprisingly, we find that the APPI scaffold greatly enhances proteolytic cleavage rates, independently of the binding loop. We draw thermodynamic additivity cycles analyzing the interdependence of P(1) and P'(2) substitutions and scaffold differences, finding multiple instances in which the contributions of these features are nonadditive. We also report the crystal structure of the mesotrypsin.APPI complex, in which we find that the binding loop of APPI displays evidence of increased mobility compared with BPTI. Our data suggest that the enhanced vulnerability of APPI to mesotrypsin cleavage may derive from sequence differences in the scaffold that propagate increased flexibility and mobility to the binding loop.
Determinants of affinity and proteolytic stability in interactions of Kunitz family protease inhibitors with mesotrypsin.,Salameh MA, Soares AS, Navaneetham D, Sinha D, Walsh PN, Radisky ES J Biol Chem. 2010 Nov 19;285(47):36884-96. Epub 2010 Sep 22. PMID:20861008[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ghosh D, Porter E, Shen B, Lee SK, Wilk D, Drazba J, Yadav SP, Crabb JW, Ganz T, Bevins CL. Paneth cell trypsin is the processing enzyme for human defensin-5. Nat Immunol. 2002 Jun;3(6):583-90. Epub 2002 May 20. PMID:12021776 doi:10.1038/ni797
- ↑ Szmola R, Kukor Z, Sahin-Toth M. Human mesotrypsin is a unique digestive protease specialized for the degradation of trypsin inhibitors. J Biol Chem. 2003 Dec 5;278(49):48580-9. Epub 2003 Sep 24. PMID:14507909 doi:10.1074/jbc.M310301200
- ↑ Salameh MA, Soares AS, Navaneetham D, Sinha D, Walsh PN, Radisky ES. Determinants of affinity and proteolytic stability in interactions of Kunitz family protease inhibitors with mesotrypsin. J Biol Chem. 2010 Nov 19;285(47):36884-96. Epub 2010 Sep 22. PMID:20861008 doi:10.1074/jbc.M110.171348
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