There are nice sentences in high school text books along the lines of 'misfolded proteins are recognized and degraded'. But in reality, it seems like a tough job to sort these proteins out. There are unfolded proteins, not completely folded proteins, completely folded proteins, and misfolded proteins - how does the cell distinguish which ones deserve to go on?
Anyway, turns out there is a way of dealing with this. Firstly, everything in biology is shape. Shape, shape, shape - John Archer, a old professor, used to stress this a lot. You can recognize when a protein is not done folding because it will display portions that it shouldn't - for example, hydrophobic areas that would be buried in a beta-sheet.
Now how to distinguish between not completely folded and misfolded? This is where sugar tagging comes in. Proteins in the ER are glycosylated in the N-terminus. Glucosyl transferase proteins recognize the hydrophobic portions of the protein, and add another sugar to the N-terminal oligosaccharide. As long as the sugar tag has at least one more glucose, the protein is recognized by calnexin and it cannot exit the ER. To escape calnexin binding, the bound glucose needs to be cleaved by glucosidase.
The proteins in ER cycle between being bound by calnexin and having a sugar cleaved, and being recognized by the glucosyl transferase and having a sugar added until they are completely folded.
This still leaves recognizing misfolded proteins - and apparently the mechanism is similar. Once the protein has spent enough time in the ER and not gotten completely folded, a sugar will be linked that will be recognized by a chaperone which will direct it to the nucleus for degradation.
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actually misfolded proteins are ubiquinated and subsequently degraded by the proteasome in the cytosol. It doesn't end up anywhere near the nucleus. Calreticulin, BiP and calnexin all actively participate in the recognition and retention of misfolded proteins.
Other chaperones like heat shock protein Hsp90 act as genetic buffers (Susan Lindquist, my MIT heroine) where subtle protein mutations are not apparent under normal conditions. The onset of stress conditions compromises hsp90 to fold these proteins properly. These mutations therefore lie dormant until stressful events are encountered and it is in these circumstances that they can be translated into harmful phenotypes. But once in a while, a few of these mutations will give rise to advantageous traits, spurring evolution.
Have fun at your viva!
Hmm.. for some reason I was sure proteasomes are found mainly in the nucleus and thus the proteins would need to end up there to be degraded. Guess I should stop writing in really weird hours..
Viva was fun indeed :)
If I didn't know better, I'd guess you just downed 8 pints and decided to write a blog...
Proteasomes are never found in the nucleus. Interestingly, the general turnover of these misfolded proteins also serve as a source of antigens for the MHC Class I assembly pathway (a very precise folding mechanism followed by the loading of specific peptides) Just goes to show that Mother Nature leaves nothing to waste. recycle, recycle, recycle :)
so did the viva examiners ask any funny questions?
Well, they did mention that I should know more biology :)
And quick look in wiki and Alberts gave me the impression however that proteasomes are present both in the nucleus and in the cytosol. Not sure who to trust - anyone can write wiki, I don't know Alberts :S
I'm yet to get to the MHC stuff - looking forward to it :)
Bruce Alberts! He wrote Molecular Biology of the Cell along with Martin Raff and a posse of famous biochemists. Great text to dive into esp if you need to know more biology :>
Proteasomes are only found in the nucleus of single cellular eukaryotes ie yeast. In multicellular organisms, it is located in the cytosol.
Yea I ended up buying the book - it looked nice and red.. Proteasomes chapter was way back in the past though - so nice to remind myself now :)
So you do know Alberts! I learnt a significant chunk of biochemistry from that book and even used it as a doorstop... they should cover MHC Class I antigen presentation somewhere as well.
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