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| | ==Human mesotrypsin complexed with HAI-2 Kunitz domain 1== | | ==Human mesotrypsin complexed with HAI-2 Kunitz domain 1== |
| - | <StructureSection load='4u32' size='340' side='right' caption='[[4u32]], [[Resolution|resolution]] 1.65Å' scene=''> | + | <StructureSection load='4u32' size='340' side='right'caption='[[4u32]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4u32]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4U32 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4U32 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4u32]] is a 2 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=4U32 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4U32 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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 1.65Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4u30|4u30]]</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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4u32 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4u32 OCA], [https://pdbe.org/4u32 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4u32 RCSB], [https://www.ebi.ac.uk/pdbsum/4u32 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4u32 ProSAT]</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=4u32 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4u32 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4u32 RCSB], [http://www.ebi.ac.uk/pdbsum/4u32 PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/SPIT2_HUMAN SPIT2_HUMAN]] Congenital sodium diarrhea. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/SPIT2_HUMAN SPIT2_HUMAN] Congenital sodium diarrhea. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SPIT2_HUMAN SPIT2_HUMAN]] Inhibitor of HGF activator. Also inhibits plasmin, plasma and tissue kallikrein, and factor XIa. [[http://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> | + | [https://www.uniprot.org/uniprot/SPIT2_HUMAN SPIT2_HUMAN] Inhibitor of HGF activator. Also inhibits plasmin, plasma and tissue kallikrein, and factor XIa. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4u32" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Hepatocyte growth factor activator inhibitor|Hepatocyte growth factor activator inhibitor]] |
| | + | *[[Trypsin 3D structures|Trypsin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Trypsin]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Radisky, E S]] | + | [[Category: Large Structures]] |
| - | [[Category: Soares, A S]] | + | [[Category: Radisky ES]] |
| - | [[Category: Wang, R]] | + | [[Category: Soares AS]] |
| - | [[Category: Enzyme kinetic]] | + | [[Category: Wang R]] |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Protease inhibitor]]
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| - | [[Category: Protein degradation]]
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| - | [[Category: Protein-protein interaction]]
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| - | [[Category: Proteolysis]]
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| - | [[Category: Serine protease]]
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| - | [[Category: Substrate specificity]]
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| Structural highlights
Disease
SPIT2_HUMAN Congenital sodium diarrhea. The disease is caused by mutations affecting the gene represented in this entry.
Function
SPIT2_HUMAN Inhibitor of HGF activator. Also inhibits plasmin, plasma and tissue kallikrein, and factor XIa.
Publication Abstract from PubMed
Mesotrypsin is an isoform of trypsin that is uniquely resistant to polypeptide trypsin inhibitors and can cleave some inhibitors rapidly. Previous studies have shown that the amyloid precursor protein Kunitz protease inhibitor domain (APPI) is a specific substrate of mesotrypsin, and that stabilization of the APPI cleavage site in a canonical conformation contributes to recognition by mesotrypsin. We hypothesized that other proteins possessing potential cleavage sites stabilized in similar conformation might also be mesotrypsin substrates. Here we evaluated a series of candidate substrates including human Kunitz protease inhibitor domains from amyloid precursor-like protein 2 (APLP2), bikunin, hepatocyte growth factor activator inhibitor type 2 (HAI2), tissue factor pathway inhibitor-1 (TFPI1), and tissue factor pathway inhibitor-2 (TFPI2), as well as E-selectin, an unrelated protein possessing a potential cleavage site displaying canonical conformation. We find that Kunitz domains within APLP2, bikunin, and HAI2 are cleaved by mesotrypsin with kinetic profiles of specific substrates. TFPI1 and TFPI2 Kunitz domains are cleaved less efficiently by mesotrypsin, and E-selectin is not cleaved at the anticipated site. Cocrystal structures of mesotrypsin with HAI2 and bikunin Kunitz domains reveal the mode of mesotrypsin interaction with its canonical substrates. Our data suggest that major determinants of mesotrypsin substrate specificity include sequence preferences at the P1 and P2' positions along with conformational stabilization of the cleavage site in the canonical conformation. Mesotrypsin upregulation has been previously implicated in cancer progression, and proteolytic clearance of Kunitz protease inhibitors offers potential mechanisms by which mesotrypsin may mediate pathological effects in cancer.
Sequence and Conformational Specificity in Substrate Recognition: Several Human Kunitz Protease Inhibitor Domains Are Specific Substrates of Mesotrypsin.,Pendlebury D, Wang R, Henin RD, Hockla A, Soares AS, Madden BJ, Kazanov MD, Radisky ES J Biol Chem. 2014 Oct 9. pii: jbc.M114.609560. PMID:25301953[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Pendlebury D, Wang R, Henin RD, Hockla A, Soares AS, Madden BJ, Kazanov MD, Radisky ES. Sequence and Conformational Specificity in Substrate Recognition: Several Human Kunitz Protease Inhibitor Domains Are Specific Substrates of Mesotrypsin. J Biol Chem. 2014 Oct 9. pii: jbc.M114.609560. PMID:25301953 doi:http://dx.doi.org/10.1074/jbc.M114.609560
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