The purpose of this blog is to explain in brief the nature of the protein Cytochrome C and also to discuss it's place in the process of cell Apoptosis, or programmed cell death. I also hope to mention briefly a few pertinent details regarding the molecule Cardiolipin, it's structure and the interactions it forms with Cytochrome C during Apoptosis. In this entry the information is becoming more specialised. As of writing a general area of study has been decided upon for the research project. This area is to analyse the electochemistry of the compounds Cytochrome C, Cardiolipin and a specific cardiolipin/cytochrome C complex which forms during apoptosis. The exact queries have not been decided upon however. Rather it is hoped that through a review of available studies and data and preliminary voltammetric analysis of these compounds specific questions will arise which suggest a direction of study. Again the information is taken from a variety of sources. Primarily these are, "Molecular Biology of the Cell" 5th Edition, "Biochemistry" Garrett and Grisham and the scientific review "Free Radical Biology and Medicine", Volume 46, Issue 11, 1 June 2009 Pages 1439-1453. A typical undergraduate knowledge of Biochemistry is assumed.
To begin with a basic description of Cytochrome C, it's function and biochemistry is needed. Cytochrome C is a member of a general class of electron transport proteins. These proteins all contain Heme groups (the Fe containing group found also in Hemeoglobin). In humans cytochromes are restricted in location to the mitochondrial inner membrane where they form part of the electron transport chain of mitochondrial respiration. As such they are an extremely redox active series of proteins. As mentioned several classes of Cytochrome exist, including Cytochromes a, b, c, and e. The classification of the cytochrome is primarily dependent on the specific heme group attatched to the protein. Thus cytochrome C (CytC henceforth) posesses an attached c heme group. As mentioned cytochromes are primarily electron transport proteins. CytC specifically acts by moving electrons between Complex III and complex IV of the electron transport chain. An overview of the electron transport chain is given below to aid in visualising this position.
(1)There are a small number of characteristics of CytC that should be mentioned. Firstly it is a relatively small protein, with a mass of 12,000 Da and consisting of the order of 100 amino acids. Secondly it is a relatively soluble protein, compared to the other repsiratory cytochromes. Thirdly, whilst it is found within the mitochondrial membrane it is not intrinsically bound to it. These factors will become important when cell apoptosis is discussed.
Cardiolipin is a phospholipid molecule found within the innner mitochondrial membrane. Specifically it is a double phospholipid which contains four fatty acid tails. The phosphate groups are bound to a central molecule of glycerol at the 1 and 3 carbon positions. In the membrane it forms a bicyclic structure such as is depicted below
(2)The DAG segment represents the residue of 2 fatty acid chains. The fatty acid chains are typically about 18 carbons in length and unsaturated. As has been mentioned cardiolipin is found primarily in the inner mitochondrial membrane where it's main function is structural. By mass it can form up to 20% of the membrane itself, arranging itself into a bilayer. However it also has a small number of other primary functions. It acts as a structural component of several of the electron transport proteins, most prominently complex IV, where the presence of cardiolipin enhances enzymatic activity. Also because of the bicyclic structure of cardiolipin it is able to act as a proton trap controlling and buffering the pH of the intermembrane space of the mitochondria.
Thus far we have discussed the focus molecules in a basic form. The area of interest for the study I am undertaking relates to a specific interaction between cardiolipin and CytC that occurs during apoptosis. A full description of the factors and processes of cell apoptosis is beyond my means and desires at this time. I shall however describe one event that occurs, within a context. Cell apoptosis, or programmed cell death. There are many factors that can trigger cell death from within the cell itself, including DNA damage or oxygen deprivation. There also exist a series of regulatory proteins including mammalian Bc12 which regulate the start of apoptosis. The most important way this is done is by controlling the release of CytC from the cellular membrane. The release of CytC is the first step in a cascade reaction that results in the closing down of cell function and the activation of executionor proteins. Within this process though a specific reaction between CytC and Cardiolipin takes place.
After CytC has been released from the mitochondrial membrane Cardiolipin begins a migration into the cytosol and the following interaction takes place. CytC and cardiolipin will bond loosely. This triggers a conformational change in the CytC complex, revealing a new active site and allowing for enzymatic activity of the protein. Specifically the process transforms the complex into a peroxidase enzyme. The enzymatic process also somehow alters the structure and nature of the cardiolipin such that, when they dissociate, the cardiolipin cannot reenter the mitochondrial membrane. This in turn generates a porous nature in the membrane which contributes to cell death. The exact mechanisms of this process are amongst the details we hope to study in this research project. For instance questions such as "Does the cardiolipin dissociate immidiately following enzymatic activity, or does it stay bound?" are interesting ones I hope to ask. However until I can perform basic voltammetry on CytC, Cardiolipin and the peroxidase complex I cannot be sure what areas will be of greatest interest to me.
Notes:
No comments:
Post a Comment