1fgd

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Revision as of 07:04, 24 March 2021

EPIDERMAL GROWTH FACTOR (EGF) SUBDOMAIN OF HUMAN THROMBOMODULIN (NMR, 11 STRUCTURES)

Structural highlights

1fgd is a 1 chain structure. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[TRBM_HUMAN] Defects in THBD are the cause of thrombophilia due to thrombomodulin defect (THPH12) [MIM:614486]. A hemostatic disorder characterized by a tendency to thrombosis.^[1] ^[2] ^[3] Defects in THBD are a cause of susceptibility to hemolytic uremic syndrome atypical type 6 (AHUS6) [MIM:612926]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.^[4] ^[5]

Function

[TRBM_HUMAN] Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated.

Publication Abstract from PubMed

The thrombin-bound structures of native peptide fragments from the fifth EGF-like domain of thrombomodulin were determined by use of NMR and transferred NOE spectroscopy. The bound peptides assume an EGF-like structure of an antiparallel beta-sheet, a novel structural motif observed for a bound peptide in protein-peptide complexes. There is a remarkable structural resiliency of this structure motif manifested in its ability to accommodate a different number of residues within the disulfide loop. Docking experiments revealed that the key contacts with thrombin are hydrophobic interactions between the side chains of residues Ile 414 and Ile 424 of thrombomodulin and a hydrophobic pocket on the thrombin surface. Residues Leu 415, Phe 419, and Ile 420, which would have been buried in intact EGF-like domains, are unfavorably exposed in the complex of thrombin with the EGF-like thrombomodulin fragment, thus providing a rationale for the enhancement of binding affinity upon the deletion of Ile 420. The unique beta-sheet structures of the bound peptides are specified by the presence of disulfide bridges in the peptides because a corresponding linear thrombomodulin fragment folds into a sheet structure with a different backbone topology. The different bound conformations for the linear and the cyclized peptides indicate that side-chain interactions within a specific environment may dictate the folding of bound peptides in protein-peptide complexes.

Structural resiliency of an EGF-like subdomain bound to its target protein, thrombin.,Hrabal R, Komives EA, Ni F Protein Sci. 1996 Feb;5(2):195-203. PMID:8745396^[6]

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

References

↑ Ohlin AK, Marlar RA. The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease. Blood. 1995 Jan 15;85(2):330-6. PMID:7811989
↑ Ohlin AK, Norlund L, Marlar RA. Thrombomodulin gene variations and thromboembolic disease. Thromb Haemost. 1997 Jul;78(1):396-400. PMID:9198186
↑ Faioni EM, Franchi F, Castaman G, Biguzzi E, Rodeghiero F. Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia. Br J Haematol. 2002 Aug;118(2):595-9. PMID:12139752
↑ Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009 Jul 23;361(4):345-57. doi: 10.1056/NEJMoa0810739. PMID:19625716 doi:10.1056/NEJMoa0810739
↑ Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010 Jun;31(6):E1445-60. doi: 10.1002/humu.21256. PMID:20513133 doi:10.1002/humu.21256
↑ Hrabal R, Komives EA, Ni F. Structural resiliency of an EGF-like subdomain bound to its target protein, thrombin. Protein Sci. 1996 Feb;5(2):195-203. PMID:8745396

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1fgd"

@@ Line 3: / Line 3: @@
 <StructureSection load='1fgd' size='340' side='right'caption='[[1fgd]], [[NMR_Ensembles_of_Models | 11 NMR models]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1fgd]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FGD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1FGD FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1fgd]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FGD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1FGD FirstGlance]. <br>
-</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=1fgd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fgd OCA], [http://pdbe.org/1fgd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1fgd RCSB], [http://www.ebi.ac.uk/pdbsum/1fgd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1fgd ProSAT]</span></td></tr>
+</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=1fgd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fgd OCA], [https://pdbe.org/1fgd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1fgd RCSB], [https://www.ebi.ac.uk/pdbsum/1fgd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1fgd ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/TRBM_HUMAN TRBM_HUMAN]] Defects in THBD are the cause of thrombophilia due to thrombomodulin defect (THPH12) [MIM:[http://omim.org/entry/614486 614486]]. A hemostatic disorder characterized by a tendency to thrombosis.<ref>PMID:7811989</ref> <ref>PMID:9198186</ref> <ref>PMID:12139752</ref>   Defects in THBD are a cause of susceptibility to hemolytic uremic syndrome atypical type 6 (AHUS6) [MIM:[http://omim.org/entry/612926 612926]]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.<ref>PMID:19625716</ref> <ref>PMID:20513133</ref>
+[[https://www.uniprot.org/uniprot/TRBM_HUMAN TRBM_HUMAN]] Defects in THBD are the cause of thrombophilia due to thrombomodulin defect (THPH12) [MIM:[https://omim.org/entry/614486 614486]]. A hemostatic disorder characterized by a tendency to thrombosis.<ref>PMID:7811989</ref> <ref>PMID:9198186</ref> <ref>PMID:12139752</ref>   Defects in THBD are a cause of susceptibility to hemolytic uremic syndrome atypical type 6 (AHUS6) [MIM:[https://omim.org/entry/612926 612926]]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.<ref>PMID:19625716</ref> <ref>PMID:20513133</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/TRBM_HUMAN TRBM_HUMAN]] Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated.
+[[https://www.uniprot.org/uniprot/TRBM_HUMAN TRBM_HUMAN]] Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

1fgd

From Proteopedia

Revision as of 07:04, 24 March 2021

EPIDERMAL GROWTH FACTOR (EGF) SUBDOMAIN OF HUMAN THROMBOMODULIN (NMR, 11 STRUCTURES)

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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