The Final Outcome
The final outcome of the quality control process of protein folding must be a native molecule that contains no errors within its conformation (Anellia et al 2008). More than 80% of proteins are improperly folded in the ER (Alberts et al 2008, p. 739-740). These misfolded proteins must be exported from the ER to the cytosol for degradation. If the proteins remain improperly folded, their conformation makes it impossible for any signal peptides present to be understood by the cell, and the protein cannot continue along the secretory pathway (Wiertz et al 1996).
Dislocation is a process whereby the misfolded proteins are transported into the cytosol instead of being broken down within the lumen of ER. However, it is not certain whether these proteins are brought by the translocons that initially carried them into the ER or through a separate dislocation channel of unknown identity (Karp, 2010 p. 456).It is thought that the decision on whether to export the protein is based on the oligosaccharide component. The oligosaccharide can act as a sort of timer for how long the protein has remained within the ER because dislocation apparatus can recognise how much degradation has occurred within the molecule by looking at the amount of mannose left in its core. If the oligosaccharide has been degraded too much then the protein is dislocated into the cytosol where its oligosaccharide chain is removed by N-glycanase and the protein is degraded by proteosomes (Alberts et al 2008, p. 739-740).
Fortunately, the level of misfolded proteins are always monitored by the protein sensors that are kept within the lumen of ER. These protein sensors are associated with the molecular chaperones (especially BiP) and thus are kept in an inactive state under normal conditions (Karp, 2010 p. 456). If too many misfolded proteins enter the cytosol, it can cause heat-shock response, in which the cytosolic chaperones must quickly be transcribed to refold proteins before cell damage can occur. Moreover, the protein sensors will unbind from the chaperones and be in an activated state. On the other hand, an accumulation of misfolded proteins in the ER can trigger an unfolded protein response. This is where the rapid transcription of genes that encode chaperone proteins occurs to either correct the folding or trigger dislocation and degradation (Alberts et al 2008, p. 739-740).
|The Slideshow above shows how Ubiquitin, a type of protein sensor, binds to a protein and then to a proteasome to aid in the degradation of a misfolded protein.|
Example in Yeast CellsIn yeast cells, for example, misfolded proteins in the ER trigger a pathway that can signal to the nucleus to reduce the amount of translation, allowing time for the correction of misfolded proteins, while also initiating the unfolded protein response. The first step in this response activates a transmembrane protein kinase in the ER, which causes autophosphorylation and oligomerisation of the kinase. This then activates an endoribonuclease domain in the molecule that cleaves cytosolic RNA at two positions to remove an intron and a RNA ligase then generates a spliced mRNA by joining the exons. The mRNA is then translated to produce a regulatory protein that activates the transcription of genes that encode components required for the unfolded protein response. The second step of this pathway involves the misfolding of proteins in the ER to activate another transmembrane kinase which uses the phosphorylation to inhibit translation initiation factor. This helps to reduce the production of new proteins by the nucleus. The third and final step involves a third regulatory protein which is initially synthesised as an integral membrane protein. When misfolding occurs, this protein is transported to the Golgi apparatus where its cytosolic domain is cleaved off. Cleavage allows it to then travel to the nucleus to help activate transcription of genes that are required for the unfolded protein response (Alberts et al 2008, p. 740-742).