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| | ==Structure of the Y46F mutant of human cytochrome c== | | ==Structure of the Y46F mutant of human cytochrome c== |
| - | <StructureSection load='3zoo' size='340' side='right' caption='[[3zoo]], [[Resolution|resolution]] 1.35Å' scene=''> | + | <StructureSection load='3zoo' size='340' side='right'caption='[[3zoo]], [[Resolution|resolution]] 1.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3zoo]] is a 4 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=3ZOO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZOO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3zoo]] is a 4 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=3ZOO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ZOO 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>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 1.35Å</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=3zoo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zoo OCA], [http://pdbe.org/3zoo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3zoo RCSB], [http://www.ebi.ac.uk/pdbsum/3zoo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3zoo ProSAT]</span></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>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></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=3zoo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zoo OCA], [https://pdbe.org/3zoo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3zoo RCSB], [https://www.ebi.ac.uk/pdbsum/3zoo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3zoo 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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 3zoo" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 3zoo" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cytochrome C 3D structures|Cytochrome C 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Hough, M A]] | + | [[Category: Large Structures]] |
| - | [[Category: Rajagopal, B S]] | + | [[Category: Hough MA]] |
| - | [[Category: Worrall, J A.R]] | + | [[Category: Rajagopal BS]] |
| - | [[Category: Apoptosis]] | + | [[Category: Worrall JAR]] |
| - | [[Category: Electron transfer]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Respiration]]
| + | |
| 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
We have investigated whether the pro-apoptotic properties of the G41S mutant of human cytochrome c can be explained by a higher than wild-type peroxidase activity triggered by phospholipid binding. A key complex in mitochondrial apoptosis involves cytochrome c and the phospholipid cardiolipin. In this complex cytochrome c has its native axial Met80 ligand dissociated from the heme-iron considerably augmenting the peroxidase capability of the heme group upon H2O2 binding. By EPR spectroscopy we reveal that the magnitude of changes in the paramagnetic heme states, as well as the yield of protein bound free radical is dependent on the phospholipid used and considerably greater in the G41S mutant. A high-resolution X-ray crystal structure of human cytochrome c was determined and in combination with the radical EPR signal analysis two tyrosine residues, Tyr46 and Tyr48, have been rationalised to be putative radical sites. Subsequent single and double tyrosine to phenylalanine mutations revealed that the radical's EPR signal, found to be similar in all variants, including G41S and wild-type, originates not from a single tyrosine residue but is instead a superposition of multiple EPR signals from different radical sites. We propose a mechanism of multiple radical formations in the cytochrome c/phospholipid complexes under H2O2 treatment, consistent with the stabilisation of the radical in the G41S mutant, which elicits a greater peroxidase activity from cytochrome c and thus has implications in mitochondrial apoptosis.
The hydrogen peroxide induced radical behaviour in human cytochrome c phospholipid complexes: Implications for the enhanced pro-apoptotic activity of the G41S mutant.,Rajagopal BS, Edzuma AN, Hough MA, Blundell KL, Kagan VE, Kapralov AA, Fraser LA, Butt JN, Silkstone GG, Wilson MT, Svistunenko DA, Worrall JA Biochem J. 2013 Oct 8. PMID:24099549[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Rajagopal BS, Edzuma AN, Hough MA, Blundell KL, Kagan VE, Kapralov AA, Fraser LA, Butt JN, Silkstone GG, Wilson MT, Svistunenko DA, Worrall JA. The hydrogen peroxide induced radical behaviour in human cytochrome c phospholipid complexes: Implications for the enhanced pro-apoptotic activity of the G41S mutant. Biochem J. 2013 Oct 8. PMID:24099549 doi:http://dx.doi.org/10.1042/BJ20130758
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