View source for Cytochrome C -Adis

==Cytochrome ''C''==
<StructureSection load='3CP5' size='340' side='right' caption='Cytochrome C with a heme and sulfate complex (PDB code [[3cp5]])' scene=''>
'''Cytochrome C''' is a [http://en.wikipedia.org/wiki/All-α_proteins all-α proteins] family protein due to its alpha helical core that is normally 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 attachments to the central heme group of Cytochrome ''C'' cause it to have different functions overall. The protein structure and function differ, but it is still considered to be a Cytochrome C protein. 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, it has been the subject of many experiments. 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 was established 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 [http://en.wikipedia.org/wiki/Heme heme] protein (or a part of the heme family) which means that it has a 
heme prosthetic group. This <scene name='Sandbox_Reserved_335/Axial/6'>heme prosthetic</scene> group is covalently bonded using thioether bonds to Histidine and Methionine residues. This heme prosthetic is four cyclic structures forming a macrocycle which coordinates functionality about a central 
iron atom. They can form different compounds by having different attachments around the 4 
pyrrole rings. Two unique structures of Cytochrome ''C'' exist naturally but both having the same general motif or <scene name='Sandbox_Reserved_335/Motif/1'>basic structure</scene>. 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 four methionine 
groups on the occupied 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 <scene name='81/814739/Bc1_complex_cytc/1'>Cytochrome ''C'' protein in mitochondria</scene>, 
one conformation of Cytochrome ''C'' is also a member of the electron transport chain in 
photosynthesis in plants. (PDB101: Molecule of the Month: Cytochrome c.) 
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.

</StructureSection>
== References ==
A.j., et al. “Three-Dimensional Structure of Cytochrome c' from Two Alcaligenes Species and the Implications for Four-Helix Bundle Structures.” Acta Crystallogr.,Sect.D, www.rcsb.org/structure/1CGN.
“Cytochrome C.” Cytochrome C - an Overview | ScienceDirect Topics, www.sciencedirect.com/topics/neuroscience/cytochrome-c.
“Cytochrome c.” Cytochrome c - Proteopedia, Life in 3D, proteopedia.org/wiki/index.php/Cytochrome_c.
Elmore, Susan. “Apoptosis: a Review of Programmed Cell Death.” Toxicologic Pathology, U.S. National Library of Medicine, 2007, www.ncbi.nlm.nih.gov/pmc/articles/PMC2117903/.
Hüttemann, Maik, et al. “The Multiple Functions of Cytochrome c and Their Regulation in Life and Death Decisions of the Mammalian Cell: From Respiration to Apoptosis.” Mitochondrion, U.S. National Library of Medicine, May 2011, www.ncbi.nlm.nih.gov/pmc/articles/PMC3075374/.
Ow, Yong-Ling P, et al. “Cytochrome c: Functions beyond Respiration.” Nature Reviews. Molecular Cell Biology, U.S. National Library of Medicine, July 2008, www.ncbi.nlm.nih.gov/pubmed/18568041.
“PDB101: Molecule of the Month: Cytochrome c.” RCSB, pdb101.rcsb.org/motm/36.
The Journal of Biochemistry, Volume 45, Issue 5, 1 May 1958, Pages 341–348,
New Journal of Science, Volume 2014, Article ID 484538, 28 pages

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