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| | <StructureSection load='6duj' size='340' side='right'caption='[[6duj]], [[Resolution|resolution]] 1.82Å' scene=''> | | <StructureSection load='6duj' size='340' side='right'caption='[[6duj]], [[Resolution|resolution]] 1.82Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6duj]] is a 2 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=6DUJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DUJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6duj]] 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=6DUJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DUJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEC:HEME+C'>HEC</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]] 1.8220272Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYCS, CYC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEC:HEME+C'>HEC</scene></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=6duj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6duj OCA], [http://pdbe.org/6duj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6duj RCSB], [http://www.ebi.ac.uk/pdbsum/6duj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6duj ProSAT]</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=6duj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6duj OCA], [https://pdbe.org/6duj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6duj RCSB], [https://www.ebi.ac.uk/pdbsum/6duj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6duj ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CYC_HUMAN CYC_HUMAN]] Defects in CYCS are the cause of thrombocytopenia type 4 (THC4) [MIM:[http://omim.org/entry/612004 612004]]; also known as autosomal dominant thrombocytopenia type 4. Thrombocytopenia is the presence of relatively few platelets in blood. THC4 is a non-syndromic form of thrombocytopenia. Clinical manifestations of thrombocytopenia are absent or mild. THC4 may be caused by dysregulated platelet formation.<ref>PMID:18345000</ref> | + | [https://www.uniprot.org/uniprot/CYC_HUMAN CYC_HUMAN] Defects in CYCS are the cause of thrombocytopenia type 4 (THC4) [MIM:[https://omim.org/entry/612004 612004]; also known as autosomal dominant thrombocytopenia type 4. Thrombocytopenia is the presence of relatively few platelets in blood. THC4 is a non-syndromic form of thrombocytopenia. Clinical manifestations of thrombocytopenia are absent or mild. THC4 may be caused by dysregulated platelet formation.<ref>PMID:18345000</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CYC_HUMAN CYC_HUMAN]] Electron carrier protein. The oxidized form of the cytochrome c heme group can accept an electron from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c then transfers this electron to the cytochrome oxidase complex, the final protein carrier in the mitochondrial electron-transport chain. Plays a role in apoptosis. Suppression of the anti-apoptotic members or activation of the pro-apoptotic members of the Bcl-2 family leads to altered mitochondrial membrane permeability resulting in release of cytochrome c into the cytosol. Binding of cytochrome c to Apaf-1 triggers the activation of caspase-9, which then accelerates apoptosis by activating other caspases. | + | [https://www.uniprot.org/uniprot/CYC_HUMAN CYC_HUMAN] Electron carrier protein. The oxidized form of the cytochrome c heme group can accept an electron from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c then transfers this electron to the cytochrome oxidase complex, the final protein carrier in the mitochondrial electron-transport chain. Plays a role in apoptosis. Suppression of the anti-apoptotic members or activation of the pro-apoptotic members of the Bcl-2 family leads to altered mitochondrial membrane permeability resulting in release of cytochrome c into the cytosol. Binding of cytochrome c to Apaf-1 triggers the activation of caspase-9, which then accelerates apoptosis by activating other caspases. |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The A51V variant of human cytochrome c is linked to thrombocytopenia 4 (THC4), a condition that causes decreased blood platelet counts. A 1.82 A structure of the A51V variant shows only minor changes in tertiary structure relative to the wild-type (WT) protein. Guanidine hydrochloride denaturation demonstrates that the global stability of the A51V variant is 1.3 kcal/mol less than that of the WT protein. The midpoint pH, pH1/2, of the alkaline transition of the A51V variant is 1 unit less than that of the WT protein. Stopped-flow pH jump experiments show that the A51V substitution affects the triggering ionization for one of two kinetically distinguishable alkaline conformers and enhances the accessibility of a high-spin heme transient. The pH1/2 for acid unfolding of the A51V variant is 0.7 units higher than for that of the WT protein. Consistent with the greater accessibility of non-native conformers for the A51V variant, the kcat values for its peroxidase activity increase by 6- to 15-fold in the pH range of 5-8 versus those of the WT protein. These data along with previously reported data for the other THC4-linked variants, G41S and Y48H, underscore the role of Omega-loop C (residues 40-57) in modulating the peroxidase activity of cytochrome c early in apoptosis. |
| | + | |
| | + | Naturally Occurring A51V Variant of Human Cytochrome c Destabilizes the Native State and Enhances Peroxidase Activity.,Lei H, Bowler BE J Phys Chem B. 2019 Oct 24;123(42):8939-8953. doi: 10.1021/acs.jpcb.9b05869. Epub, 2019 Oct 14. PMID:31557440<ref>PMID:31557440</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 6duj" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Bowler, B E]] | + | [[Category: Bowler BE]] |
| - | [[Category: Lei, H]] | + | [[Category: Lei H]] |
| - | [[Category: Apoptosis]]
| + | |
| - | [[Category: Heme]]
| + | |
| - | [[Category: Peroxidase activity]]
| + | |
| Structural highlights
Disease
CYC_HUMAN Defects in CYCS are the cause of thrombocytopenia type 4 (THC4) [MIM:612004; also known as autosomal dominant thrombocytopenia type 4. Thrombocytopenia is the presence of relatively few platelets in blood. THC4 is a non-syndromic form of thrombocytopenia. Clinical manifestations of thrombocytopenia are absent or mild. THC4 may be caused by dysregulated platelet formation.[1]
Function
CYC_HUMAN Electron carrier protein. The oxidized form of the cytochrome c heme group can accept an electron from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c then transfers this electron to the cytochrome oxidase complex, the final protein carrier in the mitochondrial electron-transport chain. Plays a role in apoptosis. Suppression of the anti-apoptotic members or activation of the pro-apoptotic members of the Bcl-2 family leads to altered mitochondrial membrane permeability resulting in release of cytochrome c into the cytosol. Binding of cytochrome c to Apaf-1 triggers the activation of caspase-9, which then accelerates apoptosis by activating other caspases.
Publication Abstract from PubMed
The A51V variant of human cytochrome c is linked to thrombocytopenia 4 (THC4), a condition that causes decreased blood platelet counts. A 1.82 A structure of the A51V variant shows only minor changes in tertiary structure relative to the wild-type (WT) protein. Guanidine hydrochloride denaturation demonstrates that the global stability of the A51V variant is 1.3 kcal/mol less than that of the WT protein. The midpoint pH, pH1/2, of the alkaline transition of the A51V variant is 1 unit less than that of the WT protein. Stopped-flow pH jump experiments show that the A51V substitution affects the triggering ionization for one of two kinetically distinguishable alkaline conformers and enhances the accessibility of a high-spin heme transient. The pH1/2 for acid unfolding of the A51V variant is 0.7 units higher than for that of the WT protein. Consistent with the greater accessibility of non-native conformers for the A51V variant, the kcat values for its peroxidase activity increase by 6- to 15-fold in the pH range of 5-8 versus those of the WT protein. These data along with previously reported data for the other THC4-linked variants, G41S and Y48H, underscore the role of Omega-loop C (residues 40-57) in modulating the peroxidase activity of cytochrome c early in apoptosis.
Naturally Occurring A51V Variant of Human Cytochrome c Destabilizes the Native State and Enhances Peroxidase Activity.,Lei H, Bowler BE J Phys Chem B. 2019 Oct 24;123(42):8939-8953. doi: 10.1021/acs.jpcb.9b05869. Epub, 2019 Oct 14. PMID:31557440[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Morison IM, Cramer Borde EM, Cheesman EJ, Cheong PL, Holyoake AJ, Fichelson S, Weeks RJ, Lo A, Davies SM, Wilbanks SM, Fagerlund RD, Ludgate MW, da Silva Tatley FM, Coker MS, Bockett NA, Hughes G, Pippig DA, Smith MP, Capron C, Ledgerwood EC. A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia. Nat Genet. 2008 Apr;40(4):387-9. Epub 2008 Mar 16. PMID:18345000 doi:ng.103
- ↑ Lei H, Bowler BE. Naturally Occurring A51V Variant of Human Cytochrome c Destabilizes the Native State and Enhances Peroxidase Activity. J Phys Chem B. 2019 Oct 24;123(42):8939-8953. doi: 10.1021/acs.jpcb.9b05869. Epub, 2019 Oct 14. PMID:31557440 doi:http://dx.doi.org/10.1021/acs.jpcb.9b05869
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