6xnk | pdb_00006xnk
Crystal structure of dimeric K72A human cytochrome c alkaline conformer
Structural highlights
DiseaseCYC_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] FunctionCYC_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 PubMedA 2.08 A structure of an alkaline conformer of the domain-swapped dimer of K72A human cytochrome c (Cytc) crystallized at pH 9.9 is presented. In the structure, Lys79 is ligated to the heme. All other domain-swapped dimer structures of Cytc have water bound to this coordination site. Part of Omega-loop D (residues 70-85) forms a flexible linker between the subunits in other Cytc domain-swapped dimer structures but instead converts to a helix in the alkaline conformer of the dimer combining with the C-terminal helix to form two 26-residue helices that bracket both sides of the dimer. The alkaline transition of the K72A human dimer monitored at both 625 nm (high spin heme) and 695 nm (Met80 ligation) yields midpoint pH values of 6.6 and 7.6, respectively, showing that the Met80 --> Lys79 and high spin to low spin transitions are distinct. The dimer peroxidase activity increases rapidly below pH 7, suggesting that population of the high spin form of the heme is what promotes peroxidase activity. Comparison of the structures of the alkaline dimer and the neutral pH dimer shows that the neutral pH conformer has a better electrostatic surface for binding to a cardiolipin-containing membrane and provides better access for small molecules to the heme iron. Given that the pH of mitochondrial cristae ranges from 6.9 to 7.2, the alkaline transition of the Cytc dimer could provide a conformational switch to tune the peroxidase activity of Cytc that oxygenates cardiolipin in the early stages of apoptosis. Alkaline State of the Domain-Swapped Dimer of Human Cytochrome c: A Conformational Switch for Apoptotic Peroxidase Activity.,Lei H, Kelly AD, Bowler BE J Am Chem Soc. 2022 Nov 8. doi: 10.1021/jacs.2c08325. PMID:36346995[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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