4. Unfolded Protein Response and Quality Control (20 points) In class, we talked

Question

4. Unfolded Protein Response and Quality Control (20 points) In class, we talked about how the Unfolded Protein Response (UPR) is triggered in eukaryotic cells when protein production exceeds the cell's folding capabilities a.) How does activation of the UPR alter gene expression in the cell? In what other ways might the cell change its behavior to aid in proper protein folding within the ER? b.) Briefly explain why it is important to monitor UPR activation when expressing a recombinant protein. c.) Given what you know about protein folding, what might be a common feature of misfolded proteins? How does the UPR pathway sense misfolded protein in the ER? d.) Briefly explain how alternative splicing is involved in mediating protein misfolding in the ER.

Explanation / Answer

a.)The UPR signalling leads to alter in gene expression in the cell, which might occur in following way: an adaptive response aimed at restoring protein-folding homeostasis by three main mechanisms: 1)transient reduction in protein translation.2)increase in the folding capacity and ER-associated degradation (ERAD7). 3)initiation of programmed cell death, when ER stress cannot be resolved.The UPR leads to transcriptional activation of genes encoding ER-resident chaperones, oxidoreductases, and ER-associated degradation (ERAD) components. Thus, UPR promotes cellular repair and adaptation by enhancing protein-folding capacity, reducing the secretory protein load, and promoting degradation of misfolded proteins. In mammalian cells, the UPR also triggers apoptosis, perhaps when adaptive responses fail.

b.)in conditions where the sub-cellular accumulation of the misfolded proteins is beyond the processing capacity by the UPR there is a co-ordinated activation of apoptosis and cell death.The expression of high levels of recombinant proteins in mammalian cell cultures has been linked to the increased UPR.so its important to monitor the level of UPR in rDNA protein expression.

c.)For many proteins, the most prominent structural motif of the functional protein in its native conformation is known as the alpha helix, a right-handed spiral coil (Pauling et al. 1951). When a protein becomes toxic, an extensive conformational change occurs and it acquires a motif known as the beta sheet. Note that the beta sheet conformation also exists in many functional native proteins, such as the immunoglobulins, but the transition from alpha helix to beta sheet is characteristic of amyloid deposits for example. The abnormal conformational transition from alpha helix to beta sheet exposes hydrophobic amino acid residues and promotes protein aggregation.misfolded proteins result when a protein follows the wrong folding pathway or energy-minimizing funnel, and misfolding can happen spontaneously. Most of the time, only the native conformation is produced in the cell. But as millions and millions of copies of each protein are made during our lifetimes, sometimes a random event occurs and one of these molecules follows the wrong path, changing into a toxic configuration.

d)the genes are actually translated into proteins and whether the alternative splice isoforms with the most extreme deletions would become misfolded

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