7ljx
From Proteopedia
Oxidized rat cytochrome c mutant (K53Q)
Structural highlights
FunctionCYC_RAT 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 (By similarity). Publication Abstract from PubMedProstate cancer is the second leading cause of cancer-related death in men. Two classic cancer hallmarks are a metabolic switch from oxidative phosphorylation (OxPhos) to glycolysis, known as the Warburg effect, and resistance to cell death. Cytochrome c (Cytc) is at the intersection of both pathways, as it is essential for electron transport in mitochondrial respiration and a trigger of intrinsic apoptosis when released from the mitochondria. However, its functional role in cancer has never been studied. Our data show that Cytc is acetylated on lysine 53 in both androgen hormone-resistant and -sensitive human prostate cancer xenografts. To characterize the functional effects of K53 modification in vitro, K53 was mutated to acetylmimetic glutamine (K53Q), and to arginine (K53R) and isoleucine (K53I) as controls. Cytochrome c oxidase (COX) activity analyzed with purified Cytc variants showed reduced oxygen consumption with acetylmimetic Cytc compared to the non-acetylated Cytc (WT), supporting the Warburg effect. In contrast to WT, K53Q Cytc had significantly lower caspase-3 activity, suggesting that modification of Cytc K53 helps cancer cells evade apoptosis. Cardiolipin peroxidase activity, which is another proapoptotic function of the protein, was lower in acetylmimetic Cytc. Acetylmimetic Cytc also had a higher capacity to scavenge reactive oxygen species (ROS), another pro-survival feature. We discuss our experimental results in light of structural features of K53Q Cytc, which we crystallized at a resolution of 1.31 A, together with molecular dynamics simulations. In conclusion, we propose that K53 acetylation of Cytc affects two hallmarks of cancer by regulating respiration and apoptosis in prostate cancer xenografts. Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and Evasion of Apoptosis.,Bazylianska V, Kalpage HA, Wan J, Vaishnav A, Mahapatra G, Turner AA, Chowdhury DD, Kim K, Morse PT, Lee I, Brunzelle JS, Polin L, Subedi P, Heath EI, Podgorski I, Marcus K, Edwards BFP, Huttemann M Cells. 2021 Apr 3;10(4). pii: cells10040802. doi: 10.3390/cells10040802. PMID:33916826[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
