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Georgia Lofts

Georgia Lofts


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About Me:Biomedical Science Graduate

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Stress Integration

Stress Integration

Processing of secreted proteins and stress integration


Approximately 1/3rd of proteins enter the secretory pathway. The endoplasmic reticulum is a key organelle for the processing of proteins. Proteins that are secreted will have a signal peptide on the N’terminus, this signal peptide is cleaved off once the protein enters the endoplasmic reticulum lumen. The signal peptide is to send the protein to the endoplasmic reticulum. Protein synthesis is closely coupled with translocation of the growing protein to the destination within the cell. When we talk about stress in the endoplasmic reticulum, we are referring to unfolded protein which is non-functional, protease sensitive and aggregation prone.


Whether a molecule is hydrophobic (water repelling) or hydrophilic (water loving) will determine its association with the endoplasmic reticulum membranes. Small molecules that are hydrophobic, such as oxygen and carbon dioxide, pass through the membrane most efficiently. Small, polarised, uncharged molecules are next in line for most efficient at passing through the membrane, for example water. Large, polarised, uncharged molecules like glucose are next. And lastly, the least efficient are charged molecules, like sodium, magnesium and calcium ions.


In the endoplasmic reticulum, proteins can undergo N-glycosylation. This is the addition of a tree of sugars using the enzyme oligosaccharide transferase. N-glycosylation is useful because it can hide the hydrophobic charges of proteins, and influence folding rates. We do not want hydrophobic regions in the protein being exposed as this leads to insoluble protein. Therefore, proteins need to be folded to only have exposed hydrophilic molecules on their outer surface, thus N-glycosylation participates in protein processing. N-glycosylation is bulky, it puts strain on the a-carbon backbone of the protein and therefore influences folding. N-glycosylation also affects the proteins activity, for example with enzymes, and with the ways in which the protein interacts with other molecules, for example antibodies. The tunica mycin blocks the synthesis of N-linked oligosaccharides. Failure to fold the protein correctly, leads to the protein being degraded.


The endoplasmic reticulum has a quality control system that ensures proteins are folded correctly. There are Bip complexes, CNX/CRT cycles (calreticulin and calnexin chaperones) and the PDI system (protein disulfide isomerase). All of which have the role of stabilising proteins, and checking they have done their job well.


There are lots of causes for stress in the endoplasmic reticulum. For example: breast cancer, leukaemia, Alzheimer’s, Parkinson’s, ALS, obesity, atherosclerosis, bacterial and viral infection. Therefore, stress can be biotic (living factors) or abiotic (non-living.) The unfolded protein response is a mechanism to get rid of ER stress and enhance the capacity of the ER. It aims to enhance folding and export of proteins, remove unfolded proteins quickly and reduce translation.


The stress sensor is IRE1. It is a transmembrane protein that under no stress exists as a monomer but becomes a dimer in times of stress. When IRE1 dimerises, the ATP binding pocket in dimer phosphorylates RNase. RNase is an enzyme that catalyses the breakdown on RNA. So RNase is activated allosterically, and it catalyses the breakdown of mRNA for the bZIP transcription factor. bZIP transcription factors regulate antioxidant proteins. Cleaved bZIP upregulates the unfolded protein response genes. If the damage is too bad, the unfolded protein response will aim towards apoptosis (programmed cell death.)



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