CYCS

Fig1. Schematic of the biogenesis and functions of mitochondrial cytochrome c. (Shalon E Babbitt, 2015)

What is CYCS protein?

CYCS gene (cytochrome c, somatic) is a protein coding gene which situated on the short arm of chromosome 7 at locus 7p15. This gene encodes a small heme protein that functions as a central component of the electron transport chain in mitochondria. The encoded protein associates with the inner membrane of the mitochondrion where it accepts electrons from cytochrome b and transfers them to the cytochrome oxidase complex. This protein is also involved in initiation of apoptosis. Mutations in this gene are associated with autosomal dominant nonsyndromic thrombocytopenia. Numerous processed pseudogenes of this gene are found throughout the human genome. The CYCS protein is consisted of 105 amino acids and CYCS molecular weight is approximately 11.7 kDa.

What is the function of CYCS protein?

CYCS is an electron carrier protein that plays a key role in cellular mitochondria. It is mainly involved in the electron transfer process of the mitochondrial respiratory chain, transferring electrons from cytochrome b to the cytochrome oxidase complex, thus completing the final electron transfer. In addition to its role in energy metabolism, CYCS proteins are also involved in the process of regulating apoptosis. When the apoptosis signal is activated, CYCS can be released from the mitochondria into the cytoplasm, form a complex with Apaf-1 and dATP, and then activate the caspase cascade, triggering programmed cell death.

CYCS Related Signaling Pathway

CYCS participate in the mitochondrial apoptotic pathway. When the apoptotic signal is triggered, CYCS are released from mitochondria into the cytoplasm, bind to APAF-1, form apoptotic bodies with Caspase-9, activate the caspase cascade reaction, and thus start the apoptosis process. Bcl-2 family proteins regulate apoptosis by controlling mitochondrial permeability. Anti-apoptotic proteins Bcl-2 and Bcl-xL inhibit CYCS release, while pro-apoptotic proteins such as Bax and Bim promote CYCS release. After release, CYCS participate in the formation of apoptotic bodies and activate the downstream caspase cascade. The release of CYCS is associated with the activation of multiple cell surface death receptors such as Fas and TNFR, which can lead to the activation of caspase-8 and -10, which in turn shear Bid to produce tBid, promoting the release of CYCS. In addition, after the release of CYCS, Smac/Diablo can bind to XIAP and inhibit its inhibition of caspase, thus promoting the apoptosis process.

CYCS Related Diseases

CYCS are associated with glomerular filtration rate, and abnormalities can lead to stomach disease. At the same time, the abnormality of CYSC gene is related to blood diseases and cardiovascular diseases. For example, the release of cytochrome C plays a role in the apoptosis of tumor cells, and the serum cytochrome C level can be used as a biomarker for some cancers, such as non-small cell lung cancer, breast cancer, and prostate cancer. Given its function in mitochondria, CYSC has also been implicated in mitochondrial diseases, liver diseases, and neurological diseases.

Bioapplications of CYCS

CYCS are used as biomarkers in serum to evaluate a variety of diseases, such as kidney disease, blood diseases, and related cancers. CYCS serve as a target for drug development, and its inhibitors are being investigated for the treatment of diseases involving apoptosis and mitochondrial dysfunction. As part of the mitochondrial electron transport chain, the study of CYCS contributes to a deeper understanding of mitochondrial function and related diseases.

Case Study 1: Neelu Yadav, 2020

Cytochrome c (Cyt c) released from mitochondria interacts with Apaf-1 to form the heptameric apoptosome, which initiates the caspase cascade to execute apoptosis. Although lysine residue at 72 (K72) of Cyt c plays an important role in the Cyt c-Apaf-1 interaction, the underlying mechanism of interaction between Cyt c and Apaf-1 is still not clearly defined. Here researchers identified multiple lysine residues including K72, which are also known to interact with ATP, to play a key role in Cyt c-Apaf-1 interaction. Mutation of these lysine residues abrogates the apoptosome formation causing inhibition of caspase activation. Using in-silico molecular docking, researchers have identified Cyt c-binding interface on Apaf-1. Although mutant Cyt c shows higher affinity for Apaf-1, the presence of Cyt c-WT restores the apoptosome activity. ATP addition modulates only mutant Cyt c binding to Apaf-1 but not WT Cyt c binding to Apaf-1.

Fig1. The far-UV (range from 190–250 nm) circular dichroism experiments were performed using recombinant Cyt c proteinis.

Fig2. Recombinant Apaf-1, procaspase-9, and procaspase-3 were reconstituted with WT or indicated mutant Cyt c alone in the presence of ATP.

Case Study 2: Viktoriia Bazylianska, 2021

Cytochrome c (Cytc) is at the intersection of metabolic switch from oxidative phosphorylation (OxPhos) to glycolysis, known as the Warburg effect, and resistance to cell death. However, its functional role in cancer has never been studied. This study shows 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, 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.

Fig3. Coomassie blue-stained gel showing the purity of recombinant Cytc.

Fig4. Oxygen consumption rate was measured in the presence of 30 nM of bovine liver COX using an Oxygraph system.

CYCS has several biochemical functions, for example, electron transporter, transferring electrons from CoQH2-cytochrome c reductase complex and cytochrome c oxidase complex activity,heme binding,metal ion binding. Some of the functions are cooperated with other proteins, some of the functions could acted by CYCS itself. We selected most functions CYCS had, and list some proteins which have the same functions with CYCS. You can find most of the proteins on our site.

CYCS has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with CYCS here. Most of them are supplied by our site. Hope this information will be useful for your research of CYCS.

APAF1;TRAF6;KRT40;CYC12;MT-CO1;GH1;EPB41;MCC;HLA-B;VHL;CASP9