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A major cellular process is the digestion of cellular components as well as extracellular molecules, it is vital for the conservation of energy. When there is something that is no longer required by the cell or that requires digestion the cell will break them down into their constituent parts which are then recycled by other pathways. This is a better idea than just getting rid of it as it conserves the energy stored in the molecules. The molecules that require breaking down vary from proteins which have been damaged or are no longer required, up to entire organelles and invading pathogens. The cell breaks down intracellular proteins by utilising a structure known as a proteasome; a large protein that breaks the peptide backbone. Extracellular proteins and other macromolecules as well as larger structures such as organelles are broken down by the lysosome which contains hydrolytic enzymes.
Figure : Image from nature reviews cancer: The proteasome a suitable antineoplastic target. The image shows the structure of the proteasome, showing the alpha and beta constituents of the 20S region (left) it also shows the 2 main 19S and 20S regions and where the 19S regions bind (right). The combination of the 19S region requires ATP.
The proteasome is an enzyme complex; this is involved in the degradation of proteins. They are found in all eukaryotes and archaea they are also found in some bacteria. They are located in both the cytosol and the nucleus. It is a 26S structure that can be split into 2 compartments, a 20S catalytic region and 2 19S regions on either end of the 20S region which are involved in regulation, this is shown in Fig.1. Also shown in Fig.1 is the structures of these regions. The 20S region is comprised of 4 rings stacked on top of each other forming a barrel. The 2
central rings are made up of 7 beta
subunits in each ring, this forms the
catalytic region with 6 active sites
located in the centre of the barrel. On
both sides there is a further ring
made up of 7 alpha subunits, which
act as docking domains for the 19S
regulatory regions. The fact that the active sites are located in the centre of the barrel means that a protein has to be loaded into the proteasome to be degraded, this prevents proteins that are still required by the cell from being broken down. Recognition of the proteins is done by the 19S regions which are located on either side of the 20S regions. They are both made up from 18 different proteins 6 of which are ATPases. The ATPases are responsible for inducing a conformational change to allow protein access. The ATPases are activated when the 19S region recognises the proteins required to be broken down, these are tagged by ubiquitin (a small protein) assisted by ubiquitin ligase. Once one ubiquitin has been added to the protein further ubiquitins are added to form a polyubiquitin chain. The 19S region binds the polyubiquitin chain and starts to unfold the protein and moves it into the catalytic core. Approximately 1/3 of newly formed polypeptide chains are tagged for degradation.
There are 3 different types of beta subunits, each have specificity about them however they all work in the same way. The active site contains a threonine residue, the N-terminus acts as a nucleophile. The N-terminus attacks the carbonyl group of the peptide bond to form an acyl link. This forms fragments of 7-9 amino acids in length; these are then released and are further degraded by cytosolic proteases to form single amino acids which are recycled. The ubiquitin tag is also removed and is also recycled. The proteasome is the final apparatus involved in the protein quality control mechanism. It removes proteins that have been damaged or are no longer required by the cell.
Lysosomes are membrane bund organelles found in all eukaryotic cells. However they are more concentrated in animals. They contain approximately 40 different hydrolytic enzymes which are involved in the breakdown of many molecules. These are located in the cytosol, in plants and yeast the vacuole is responsible for most of the processes that the lysosome undertakes. They are involved in the degradation of damaged organelles, as well as endocytosed macromolecules and pathogens. The hydrolytic enzymes in the lysosome vary from amylases for the breakdown of carbohydrates, nucleases for the breakdown of nucleic acids and proteases for proteins as well as many others. The enzymes in the lysosome require an acidic pH of around 5; the lysosome keeps the inside at this pH via an H+ and Cl- ATPase pump located on the surface of the lysosome. If the lysosome was to rupture or leak these proteins will be inactive in the slightly alkaline cytosol preventing their action on required molecules. The enzymes are produced in the cytosol or are co-translationally synthesised into the endoplasmic reticulum.
From the endoplasmic reticulum they are transported to the Cis-Golgi in a transport vesicle, they travel through the Golgi and are modified by the addition of a polysacharride chains. At the Trans-Golgi the enzymes are packaged into vesicles which become the lysosome and then they are released and are free to undertake their processes (Fig.2). When the breakdown products of the macromolecules and other structures are present in the lysosome they are transported out of the structure via transport proteins in the membrane, this allows for them to be recycled and used in other pathways. 4.11B Lysosome formation and.JPG
Figure : Shows the production of a lysosome from the ER to the Golgi and release. It also shows the lysosomes action on a food vacuole and a damaged organelle. Even though both the proteasome and lysosome are involved in the breakdown in proteins, they proteins they do breakdown are different. The lysosome is involved in the breakdown of endocytosed proteins from the diet and cell surface proteins by merging with the cell membrane. The endocytosed proteins supply the cell with essential amino acids. Whereas the proteasome is involved in the degradation of proteins that have been synthesised by the cell, these are involved in many different mechanisms. They terminate transcription factors and metabolic enzymes, this allows for cellular differentiation, as well as this they allow for the continuation of the cell cycle by the removal of cyclins. As well as this there are many other processes which they assist in. The proteasome will only remove a misfolded protein due to mutations or damage if it cannot be repaired by a chaperone.