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The cell cycle, also known as the cell division cycle and is a process in which a series of stages plays out and promotes cell division and replication. In Eukaryotic cells the cell cycle can be split into two main processes, this first being interphase - the process of cell growth which includes DNA replication which is then followed by the mitotic or M phase, this phase is the division stage, the main cell splits into two daughter cells (diploid)..Protein degradation is the process of controlled degradation of proteins that have either been folded wrongly or have come to the end of their biological life and need to make way for newly synthesised proteins in the cell. Throughout this essay the cell cycle will be discussed further as well as the controlled protein degradation which is also known as proteolysis and how process is important in regulating the cell cycle and the pathways involved.
For a successful progression through the cell division cylce processeses such as DNA replication, division of the nucleus, spindle fibre assembly and cytokinesis. In order to coordinate these processes eukaryotic cells have evolved a mechanism that is driven by Cdks (cyclin dependant kinases), These molecules ensure that the cell cycle does not reverse on itself by phosphorylating proteins to ensure that the cell cycle continues to go forward and doesn't go back on itself. As proteins that are important for the previous stage the cell has evolved the strategy of degrading that protein which stops the cell cycle going back on itself.
Protein degradation (General)
Selective destruction of intracellular proteins is the ultimate mechanism that ensures high quality proteins are contained in the cell. Selective protein destruction is named proteolysis. Proteolysis is very important in a cell for many reasons - In a cell environment homeostasis has to maintained if the cell is to function correctly. Proteins which have been misfolded due to mutations need to be deleted as they can become aggressive to the cell. Aggregate proteins that are not degraded can become dangerous to humans and can cause severe human diseases such as sickle-cell anaemia for example. Other than deleting mutated proteins, protein degradation ensures that regulatory proteins can be degraded when their time in the cell cycle comes. Proteolysis is hazardous if not used in the correct way this is why compartmentalization has come into effect to ensure that healthy or needed protein do not become degraded. The term compartmentalization refers to the confinement of the action sites of the proteasome that can only be accessed when they have a specific degradation signal. Most of these compartments are in the form of membrane bound vesicles named lysosomes but in this case a proteasome degrades the protein. Lysosomes are membrane bound vesicles which engulf substares which are then degraded by digestive enzymes contained within the lysosome. Proteasomes are barrel shaped structures which consists of four rings surrounding a central pore. Each one of these rings is composed of seven separate proteins, the two outer rings are made up of seven beta subunits which contain six protease active sites, as these active sites are structured on the inside of the molecule this means that the target protein needing degraded has to enter the central pore of the molecule. As well as the inner rings a proteasome also has two outer rings which again consists of seven sub units only this time they are alpha subunits, the main function of these is to act as channels or gates allowing the target protein to enter the central pore where it will begin degradation.
The cell cycle is regulated by a serine/threonine family of protein kinases; these are named cyclin dependant kinases (cdks) due to their need for smaller units called cyclins.
Protein ubiquination is divided into three important stages, ubiquitin activation, ubiquitin conjucation and ubiquitin-protein ligation. The firsat stage, ubiquitin activation first starts with a 76 amino acid protein named Ubiquitin and the joining of its ATP dependant carboxyl terminal (COOH)end to an enzyme named E1 (ubiquitin-activating enzyme). This then transfers the ubiquitin to one of many ubiquitin-conjugating enzymes named E2. The E2 enzyme then collaborates with a very specific ubiquitin protein ligase named E3. The E3 enzyme then codes for the formation of a peptide bond between the carboxyl terminal glycine of the ubiquitin protein and the target protein side chain lysine. Once this part has been done more lysines are added to the ubiquitin molecule or the protein being targeted, this results in polymers made of ubiquitin on the surface of the target protein, all this leads to the final step in ubiquination which ends in the degradation of the target protein. 26S is a proteasome which recognises the ubiquitin chains on the protein surface, this proteasome then degrades the protein into smaller peptides. Substrates relevant to ubiquination in the cell cyle are divided into two categories, the first being that the substrate is required to be degraded for the cell cycle to progress for example B-type cyclins, the second class is recognised not being essential for the substrate to be degraded but is important in the cell homeostasis such as G1 cyclins.
SCF (SKP1/Cullin/f-box complex)APC(anaphase promoting complex)
Both SCF and APC are both E3 ubiquitin ligases which recognise target substrates, both these molecules are related through evolution . SCF and APC are multiprotein complexes. The anaphase promoting complex is responsible for the degrading of the mitotic cyclins, the second role of APC is to ubiquinate the anaphase inhibitor securin. Securin is an subunit of separase which is a protease that's destroys the sister chromatids joining at the transiton from anaphase to metaphase.
Controlling the cell cycle
Repetitive variation in the action of CDK (cyclin dependant kinases) drives the eukaryotic cell cycle forward. Proteolysis not only regulates the CDK activity by the degradation of the CDK inhibitors and activators but also triggers the shift from mataphase to anaphase in the cycle. Protein degradation is controlled by two ubiquitin conjugation pathways in the cell cyle the first requiring CDC34 this starts DNA replication by degrading the CDK inhibitor. The second pathway involved in the cell cycle involves a large complex protein named the anaphase promoting complex which is also known as a cyclosome, this cyclosome starts the process known as chromosome segregation and eventually leads to the exit of mitosis by degrading the anaphase inhibitors and mitotic cyclins.
In conclusion this essay has reviewed the process of protein degradation commonly known as proteolysis and how this step by step process is crucial in the cell cycle and stops back tracking, driving the cell cycle forward by degradation of proteins that were important in the former stage of the cell cycle and in turn this stops the cycle from returning to the former stage ensuring progress is achieved. Proteolysis