Cytochrome C -Adis

Cytochrome C is a heme family protein that is generally located within the space between the inner mitochondrial membrane and outer mitochondrial membrane. It is a vital part of the respiratory cycle taking a key role in the transfer of electrons from complex III to complex IV. Cytochrome C is also one of the initiation proteins for apoptosis or cell death. One method of apoptosis is completely reliant on the release of cytochrome C into the cytosol in order to initiate apoptosis. Different conformations of Cytochrome C cause it to have different functions overall. The composition of Cytochrome C is relatively quite simple in comparison to other major proteins since approximately 20% of its residues being Lysine (The Journal of Biochemistry). Cytochrome C, since it is so small, is one of the most experimented on proteins out there. The structure being easy to map out and capable of being edited makes it a popular protein to experiment with even though it has the heme group causing some issues and complexity. However simple, it is a crucial protein for overall function in all Eukaryotes (New Journal of Science). It is also an ancient protein that established itself in the earliest stages of life but was not discovered until 1886 by Charles A. Macmunn. Cytochrome C was also rediscovered in 1925 by Charles Keilin. Since then, many have experimented with the inhibition of cytochrome C release which has shown promising results in therapeutic potential for Huntington’s disease. Others have used Cytochrome C in cancer research using it for its apoptosis function. The relatively small protein has a diverse job description causing it to be one of the most versatile experimental proteins known to this day.

Structure

Cytochrome C is a heme protein (or a part of the heme family) which means that it has a heme prosthetic group. This heme prosthetic group is covalently bonded using thioether bonds to cysteine residues. This heme prosthetic is four cyclic structures forming a circle around a central iron atom. They can form different compounds by having different attachments around the 4 pyrrole rings. Two conformations of cytochrome C exist naturally. In the monoheme form, the other axial position is usually left empty however, it can be occupied by other molecules such as histidine or lysine. Leaving the location empty prevents steric hindrance and allows for easier attachment. The other forms contain anywhere from one to seven methionine groups on what we perceive the left side of the heme group. When drawn out, the structure of Cytochrome C looks vertically and horizontally symmetrical due to the central heme group prior to adding side chains. The side chains which determine overall function are branched off of the central heme group and vary depending on the proteins location in the cell. They can have one form of side chain branching off at multiple locations, like a methionine attaching at multiple locations, or it can have different types of attachments, like one methionine at a location and then a lysine or histidine at another location. (Three-Dimensional Structure of Cytochrome c' )

Function

Cytochrome C function is dependent on the conformation of the structure it is portraying at the time which is primarily determined by the location of the cytochrome c protein within the cell. Monoheme cytochrome C, which is primarily found in the mitochondria of the cell, functions in eukaryotes the electron transport chain. Cytochrome C is an electron transfer protein during the bc1 complex of the electron transport chain. (See below for more detailed information) Involving identical structure to the cytochrome C protein in , one conformation of cytochrome C is also a member of the electron transport chain in photosynthesis in plants and cyanobacteria. (PDB101: Molecule of the Month: Cytochrome c.) You can also find it in a Heme C form which is a membrane bound protein that converts O2 into two water molecules using the electrons. Cytochrome C is also a main signaling factor for apoptosis of cells. In the intrinsic pathway of apoptosis, Cytochrome C plays a key role in the initiation of cell death. Without Cytochrome C, the cell could not release the protein into the cytosol which at high volumes leads to intrinsic apoptosis. (see below for more detailed information on this function)

Role in Apoptosis

Apoptosis is one form of programmed cell death in multicellular organisms. There are multiple tags that are on a cell that signal for it to go to the apoptotic pathway. Once tagged, cells go through a biochemical pathway that changes the cells morphology and leads to the “suicide” or self death of the cell. A cell can go through either an extrinsic or an intrinsic pathway in order to perform apoptosis. During the extrinsic pathway, an immune response is initiated by killer lymphocytes which cause an apoptotic cascade. (Apoptosis: a Review of Programmed Cell Death) Cytochrome C takes play in the intrinsic pathway. This is when a stimulus causes Cytochrome C to be released into the Cytosol. Once cytochrome C is in the cytosol, it is recognized and bound to apoptotic factors which are then activated forming the apoptosome complex. Then caspases join in and are activated which result in a caspase cascade forcing apoptosis. (Cytochrome c: Functions beyond Respiration.) Also over time while a cell is getting old, it has degradation of its membranes. This degradation also leads to the release of Cytochrome C which would signal that the cell is old and ready to be killed off. Without Cytochrome C, intrinsic apoptosis would not be possible because the apoptotic factors would never be activated. Same as if there are mutations in cytochrome C causing it to be unable to permeate through the membrane, or if there is a mutation that increases the permeability of it through the membrane, the apoptotic pathway would be accelerated or inhibited. (Cytochrome C Proteopedia)

Purpose in ETC and Photosynthesis

Cytochrome C also plays a key role in the Electron Transport Chain in mitochondria. It is one of the many electron carriers in the electron transport chain but quite a vital one. The heme group portion of Cytochrome C accepts the electrons from the bc1 complex and then carries the electrons to complex IV. Once at complex IV, the cytochrome C release their electron that they are carrying and it is given to the Cytochrome C Oxidase enzyme. This enzyme accumulates 4 electrons and transfers them to one dioxygen molecule in order to make two molecules of water. It is also found within the thylakoid membrane in the chloroplast of plants and green algae. In photosynthesis, Cytochrome C is one of the steps that transfers electrons from photosystem II to photosystem I. Later in the cycle, the electrochemical gradient will then be used in order to synthesize ATP from ADP. (The Multiple Functions of Cytochrome c)

Medical/Research Purposes

A proposal by many research scientists has been to regulate mitochondrial energy production and ROS production through the phosphorylation of cytochrome C. It has been observed that Tyr48Glu phosphomimetic mutant Cytochrome c reacts with CcO, but it is partially inhibited which leads to controlled respiration. (The Multiple Functions of Cytochrome c) They are proposing that “this effect plays an essential role in the prevention of ROS under healthy conditions.” There is evidence when cellular stress is happening, Cytochrome C then becomes phosphorylated. Once dephosphorylated, controlled respiration ceases which then sets up Cytochrome C to initiate apoptosis. They report that the cellular stress causes mitochondrial membrane potential differences and it needs to be taken into account to be able to determine the risks behind changes in OxPhos activity. The study focuses mainly on the phosphorylation of Cytochrome C, but acknowledges the fact that other factors may also be affected through their actions. Others have began to focus their research on major diseases such as Huntington’s disease or diverse forms of cancer. In a post by the New Journal of Science, they report that the closest that anyone has come to a universal cure for cancers has been with the use of the apoptotic function of cytochrome C. They went on to explain that tricking the body into believing these cancerous cells are ready to die, they could negate the effects of the ineffective p53 gene.