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19. Protein Folding and Quality Control.pdf

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Biology (Sci)
BIOL 200
Richard Roy

Deademptathi-dependent ー... oaaa. -Agg- Deademptathi - dependent ー ... oaaa . -Agg-Naveen Sooknanan McGill Fall 2011 Protein Folding and Quality Control: mRNAs are inherently the most stable type of RNA because of their 5’ cap and 3’ poly (A) tail. This is because there are 3 degradation pathways through which and mRNA molecule can be degraded:  A decapping pathway involves exonucleic digestion of the 5’ cap, following by exonucleic decay of the entire molecule  A deadenylation pathway involves exonucleic shortening of the poly (A) tail followed by exonucleic decay  An endonucleic pathway involved endonucleic cleavage of the mRNA, followed by digestion by exonucleases  Therefore, mRNAs with longer poly (A) tails tend to last longer than mRNAs with shorter ones One method of protein quality control involves the first round of translation, called the pioneering round  Normally, all mRNA binding proteins are removed during mRNA remodelling, leaving only the ribosome and other proteins required for translation (such as PABPI if needed)  If any of these proteins are left on the mRNA, the ribosome will not be able to translate past these area, resulting in an in frame stop o These proteins could be SR proteins left over from splicing within the nucleus, poly (A) binding proteins, cap binding proteins, and export proteins  If an in frame stop occurs on the pioneering round, the cell recognizes these mRNAs and disposes of them because they can be dangerous  This process is known as nonsense mediated decay (NMD) o NMD ensures that all mRNAs actively transcribing within the cell of are proper quality  An example of NMD is in TFs (transcription factors) which could lose their activating domain but keep the DNA binding domain o This could result in these mutant TFs filling up all the TF binding stops on DNA while not actually activating transcription of these genes o This is a dominant negative mutation resulting in the loss of expression of this gene o To prevent this, the cell undergoes NMD to degrade the mutant TF mRNA as soon as possible Proteins get their vast array of functions from their ability to fold themselves into different shapes depending on their amino acid sequences  This folding happens co-incidentally or right after synthesis and is often dependant on the amino acid sequence o This folding occurs so that it assumes the lowest energy state in its active form 1Unfolded protein Ribosome peraNy foldedor Unfolding Surface Native protein Unfolded protein Ribosome peraNy foldedor Unfolding Surface Native proteinNaveen Sooknanan McGill Fall 2011 o This folding occurs through hydrophobic interactions of nonpolar aa’s and hydrophilic interactions between polar aa’s  Denaturing proteins, either by heat, pH change, etc. removed these interactions and returns the polypeptide to a linear form o Many of these polypeptides, such as Guanidine HCl or β Mercaptoethanol are able to renature themselves (similar to DNA) once the denaturing agent is removed  Sometimes, other proteins are required to help more complex proteins fold correctly  Since the proteins are almost always in an aqueous solution (the intracellular fluid), nonpolar amino acids tend to form the core of the protein while they are protected by layers of polar amino acids (charged or uncharged) for protection o This also increases the protein’s solubility within the cell’s aqueous interior Sometimes, cells undergo heat shock which can inhibit the correct folding of proteins. This heat shock can be caused by things like a fever  In order to keep the proteins in correct order, molecular chaperones called heat shock proteins (HSPs) are increased in concentration significantly during a fever o HSPs help proteins carry out correct folding during an heat shock event o This is useful during a fever, because bacterial proteins cannot survive in a heat shock, causing them to die out, while the body’s proteins remain unharmed  In an ATP bound state, an HSP such as HSP70 or DnaK binds an unfolded polypeptide onto its substrate binding domain  An enzyme called DnaJ or Hsp40 causes the phosphorylation of ATP which causes a conformational change to the HSP o This conformational change catalyzes the correct folding of the protein substrate  Through another enzyme called GrpE or BAG1, another ATP is added onto the nucleotide binding domain of the HSP which returns it to its “loose” conformation o This releases the folded protein and initiates the binding of another unfolded polypeptide  HSPs are nonspecific and can bind with a wide variety of proteins o HSPs prevent polypeptides from undergoing incorrect folding, or from folding with other polypeptides Another type of protein which helps in folding is called a chaperonin, such as GroEL in bacteria. Chaperonins, unlike HSPs have very specific substrates and are used constantly (not only during a fever) for complex proteins which require very intricate folding patterns  Chaperonins are giant molecular structure resembling chambers which catalyze the correct folding of various proteins o They can also correct misfolded proteins  TriC is a chaperonin in humans, but is poorly understood o It is thought to act like GroEL, a well understood bacterial chaperonin 2GroEL "relaxed GroEL 'tight" conformation Laughing Death GroEL "relaxed GroEL 'tight" conformation Laughing DeathNaveen Sooknanan McGill Fall 2011  GroEL exists in two conformations: a loos ATP bound state and a tight hydrolyzed state o It accepts an unfolded or misfolded polypeptide in its ATP bound site o Through the binding of a GroES cap, ATP is hydrolyzed, causing a conformational tightening  The protein is then correctly folded and the whole process disassembles Several neurological pathologies are related to a buildup of misfolded proteins which form aggregates called “plaques”, especially in brain tissue  The misfolded proteins tend to complex with each other to form these plaques which come out of solution to form a solid aggregate o This can ca
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