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| - | [[Image:1hdl.gif|left|200px]]<br /> | |
| - | <applet load="1hdl" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1hdl" /> | |
| - | '''LEKTI DOMAIN ONE'''<br /> | |
| | | | |
| - | ==Overview== | + | ==LEKTI domain one== |
| - | We have determined the solution structures of recombinant domain 1 and, native domain 6 of the multi-domain Kazal-type serine proteinase inhibitor, LEKTI using multi-dimensional NMR spectroscopy. While two of the 15, potential inhibitory LEKTI domains contain three disulfide bonds typical, of Kazal-type inhibitors, the remaining 13 domains have only two of these, disulfide bridges. Therefore, they may represent a novel type of serine, proteinase inhibitor. The first and the sixth LEKTI domain, which have, been isolated from human blood ultrafiltrate, belong to this group. In, spite of sharing the same disulfide pattern and a sequence identity of, about 35% from the first to the fourth cysteine, the two proteins show, different structures in this region. The three-dimensional structure of, domain 6 consists of two helices and a beta-hairpin structure, and closely, resembles the three-dimensional fold of classical Kazal-type serine, proteinase inhibitors including the inhibitory binding loop. Domain 6 has, been shown to be an efficient, but non-permanent serine proteinase, inhibitor. The backbone geometry of its canonical loop is not as well, defined as the remaining structural elements, providing a possible, explanation for its non-permanent inhibitory activity. We conclude that, domain 6 belongs to a subfamily of classical Kazal-type inhibitors, as the, third disulfide bond and a third beta-strand are missing. The, three-dimensional structure of domain 1 shows three helices and a, beta-hairpin, but the central part of the structure differs remarkably, from that of domain 6. The sequence adopting hairpin structure in domain 6, exhibits helical conformation in domain 1, and none of the residues within, the putative P3 to P3' stretch features backbone angles that resemble, those of the canonical loop of known proteinase inhibitors. No proteinase, has been found to be inhibited by domain 1. We conclude that domain 1, adopts a new protein fold and is no canonical serine proteinase inhibitor. | + | <StructureSection load='1hdl' size='340' side='right'caption='[[1hdl]]' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1hdl]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HDL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1HDL FirstGlance]. <br> |
| | + | </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=1hdl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hdl OCA], [https://pdbe.org/1hdl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1hdl RCSB], [https://www.ebi.ac.uk/pdbsum/1hdl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1hdl ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/ISK5_HUMAN ISK5_HUMAN] Defects in SPINK5 are the cause of Netherton syndrome (NETH) [MIM:[https://omim.org/entry/256500 256500]. NETH is an autosomal recessive congenital ichthyosis associated with hair shaft abnormalities and anomalies of the immune system. Typical features are ichthyosis linearis circumflexa, ichthyosiform erythroderma, trichorrhexis invaginata (bamboo hair), atopic dermatitis, and hayfever. High postnatal mortality is due to failure to thrive, infections and hypernatremic dehydration.<ref>PMID:10835624</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/ISK5_HUMAN ISK5_HUMAN] Serine protease inhibitor, probably important for the anti-inflammatory and/or antimicrobial protection of mucous epithelia. Contribute to the integrity and protective barrier function of the skin by regulating the activity of defense-activating and desquamation-involved proteases. Inhibits KLK5, it's major target, in a pH-dependent manner. Inhibits KLK7, KLK14 CASP14, and trypsin.<ref>PMID:10419450</ref> <ref>PMID:17596512</ref> <ref>PMID:20533828</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hd/1hdl_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <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/main_output.php?pdb_ID=1hdl ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | We have determined the solution structures of recombinant domain 1 and native domain 6 of the multi-domain Kazal-type serine proteinase inhibitor LEKTI using multi-dimensional NMR spectroscopy. While two of the 15 potential inhibitory LEKTI domains contain three disulfide bonds typical of Kazal-type inhibitors, the remaining 13 domains have only two of these disulfide bridges. Therefore, they may represent a novel type of serine proteinase inhibitor. The first and the sixth LEKTI domain, which have been isolated from human blood ultrafiltrate, belong to this group. In spite of sharing the same disulfide pattern and a sequence identity of about 35% from the first to the fourth cysteine, the two proteins show different structures in this region. The three-dimensional structure of domain 6 consists of two helices and a beta-hairpin structure, and closely resembles the three-dimensional fold of classical Kazal-type serine proteinase inhibitors including the inhibitory binding loop. Domain 6 has been shown to be an efficient, but non-permanent serine proteinase inhibitor. The backbone geometry of its canonical loop is not as well defined as the remaining structural elements, providing a possible explanation for its non-permanent inhibitory activity. We conclude that domain 6 belongs to a subfamily of classical Kazal-type inhibitors, as the third disulfide bond and a third beta-strand are missing. The three-dimensional structure of domain 1 shows three helices and a beta-hairpin, but the central part of the structure differs remarkably from that of domain 6. The sequence adopting hairpin structure in domain 6 exhibits helical conformation in domain 1, and none of the residues within the putative P3 to P3' stretch features backbone angles that resemble those of the canonical loop of known proteinase inhibitors. No proteinase has been found to be inhibited by domain 1. We conclude that domain 1 adopts a new protein fold and is no canonical serine proteinase inhibitor. |
| | | | |
| - | ==Disease==
| + | Homologous proteins with different folds: the three-dimensional structures of domains 1 and 6 of the multiple Kazal-type inhibitor LEKTI.,Lauber T, Schulz A, Schweimer K, Adermann K, Marx UC J Mol Biol. 2003 Apr 18;328(1):205-19. PMID:12684009<ref>PMID:12684009</ref> |
| - | Known diseases associated with this structure: Atopy OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605010 605010]], Netherton syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605010 605010]]
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 1HDL is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1HDL OCA].
| + | </div> |
| - | | + | <div class="pdbe-citations 1hdl" style="background-color:#fffaf0;"></div> |
| - | ==Reference== | + | == References == |
| - | Homologous proteins with different folds: the three-dimensional structures of domains 1 and 6 of the multiple Kazal-type inhibitor LEKTI., Lauber T, Schulz A, Schweimer K, Adermann K, Marx UC, J Mol Biol. 2003 Apr 18;328(1):205-19. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12684009 12684009]
| + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Adermann, K.]]
| + | [[Category: Lauber T]] |
| - | [[Category: Forssmann, W.G.]]
| + | [[Category: Marx UC]] |
| - | [[Category: Lauber, T.]] | + | [[Category: Roesch P]] |
| - | [[Category: Marx, U.C.]] | + | |
| - | [[Category: Roesch, P.]] | + | |
| - | [[Category: Schulz, A.]]
| + | |
| - | [[Category: putative serine proteinase inhibitor]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:16:31 2007''
| + | |
| Structural highlights
Disease
ISK5_HUMAN Defects in SPINK5 are the cause of Netherton syndrome (NETH) [MIM:256500. NETH is an autosomal recessive congenital ichthyosis associated with hair shaft abnormalities and anomalies of the immune system. Typical features are ichthyosis linearis circumflexa, ichthyosiform erythroderma, trichorrhexis invaginata (bamboo hair), atopic dermatitis, and hayfever. High postnatal mortality is due to failure to thrive, infections and hypernatremic dehydration.[1]
Function
ISK5_HUMAN Serine protease inhibitor, probably important for the anti-inflammatory and/or antimicrobial protection of mucous epithelia. Contribute to the integrity and protective barrier function of the skin by regulating the activity of defense-activating and desquamation-involved proteases. Inhibits KLK5, it's major target, in a pH-dependent manner. Inhibits KLK7, KLK14 CASP14, and trypsin.[2] [3] [4]
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
We have determined the solution structures of recombinant domain 1 and native domain 6 of the multi-domain Kazal-type serine proteinase inhibitor LEKTI using multi-dimensional NMR spectroscopy. While two of the 15 potential inhibitory LEKTI domains contain three disulfide bonds typical of Kazal-type inhibitors, the remaining 13 domains have only two of these disulfide bridges. Therefore, they may represent a novel type of serine proteinase inhibitor. The first and the sixth LEKTI domain, which have been isolated from human blood ultrafiltrate, belong to this group. In spite of sharing the same disulfide pattern and a sequence identity of about 35% from the first to the fourth cysteine, the two proteins show different structures in this region. The three-dimensional structure of domain 6 consists of two helices and a beta-hairpin structure, and closely resembles the three-dimensional fold of classical Kazal-type serine proteinase inhibitors including the inhibitory binding loop. Domain 6 has been shown to be an efficient, but non-permanent serine proteinase inhibitor. The backbone geometry of its canonical loop is not as well defined as the remaining structural elements, providing a possible explanation for its non-permanent inhibitory activity. We conclude that domain 6 belongs to a subfamily of classical Kazal-type inhibitors, as the third disulfide bond and a third beta-strand are missing. The three-dimensional structure of domain 1 shows three helices and a beta-hairpin, but the central part of the structure differs remarkably from that of domain 6. The sequence adopting hairpin structure in domain 6 exhibits helical conformation in domain 1, and none of the residues within the putative P3 to P3' stretch features backbone angles that resemble those of the canonical loop of known proteinase inhibitors. No proteinase has been found to be inhibited by domain 1. We conclude that domain 1 adopts a new protein fold and is no canonical serine proteinase inhibitor.
Homologous proteins with different folds: the three-dimensional structures of domains 1 and 6 of the multiple Kazal-type inhibitor LEKTI.,Lauber T, Schulz A, Schweimer K, Adermann K, Marx UC J Mol Biol. 2003 Apr 18;328(1):205-19. PMID:12684009[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, Bonafe JL, Wilkinson J, Taieb A, Barrandon Y, Harper JI, de Prost Y, Hovnanian A. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet. 2000 Jun;25(2):141-2. PMID:10835624 doi:10.1038/75977
- ↑ Magert HJ, Standker L, Kreutzmann P, Zucht HD, Reinecke M, Sommerhoff CP, Fritz H, Forssmann WG. LEKTI, a novel 15-domain type of human serine proteinase inhibitor. J Biol Chem. 1999 Jul 30;274(31):21499-502. PMID:10419450
- ↑ Deraison C, Bonnart C, Lopez F, Besson C, Robinson R, Jayakumar A, Wagberg F, Brattsand M, Hachem JP, Leonardsson G, Hovnanian A. LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol Biol Cell. 2007 Sep;18(9):3607-19. Epub 2007 Jun 27. PMID:17596512 doi:10.1091/mbc.E07-02-0124
- ↑ Bennett K, Callard R, Heywood W, Harper J, Jayakumar A, Clayman GL, Di WL, Mills K. New role for LEKTI in skin barrier formation: label-free quantitative proteomic identification of caspase 14 as a novel target for the protease inhibitor LEKTI. J Proteome Res. 2010 Aug 6;9(8):4289-94. doi: 10.1021/pr1003467. PMID:20533828 doi:10.1021/pr1003467
- ↑ Lauber T, Schulz A, Schweimer K, Adermann K, Marx UC. Homologous proteins with different folds: the three-dimensional structures of domains 1 and 6 of the multiple Kazal-type inhibitor LEKTI. J Mol Biol. 2003 Apr 18;328(1):205-19. PMID:12684009
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