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| “Drips” (Susan S. Roberts. 2007) |
A while ago, I posted a brief extract from a 2008 paper from Drummond & Wilke1 that determined that 18% of proteins have at least one misincorporated amino acid, and linked that to my commentary on Yewdell’s “DRiPs” hypothesis here (also see here for more commentary). At the time, I took the 18% figure as surprisingly good support for Yewdell’s notion that a large fraction of proteins are misfolded (and therefore rapidly degraded) on translation.
Claus Wilke just gave a really interesting seminar here and I had a chance to chat with him about this paper and much more, so I want to clarify that he does not take this finding as support for (or disproof of) the DRiPs hypothesis. Claus’s point, supported more strongly in subsequent papers,2 is that proteins incorporate this level of aberrant amino acids without experiencing misfolding as a consequence. He argues that genes have evolved enough robustness in their folding parameters that they can and do tolerate this level of mistranslation. Since Yewdell’s hypothesis is based on mis-folding, I think Claus’s data are more or less neutral with regard to DRiPs.
- Mistranslation-Induced Protein Misfolding as a Dominant Constraint on Coding-Sequence Evolution. D. Allan Drummond and Claus O. Wilke. Cell 134:341-352 (25 July 2008) doi:10.1016/j.cell.2008.05.042[↩]
- For example: The evolutionary consequences of erroneous protein synthesis. D. Allan Drummond & Claus O. Wilke. Nature Reviews Genetics 10, 715-724 (October 2009) doi:10.1038/nrg2662[↩]
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Presumably the robustness against misincorporation of amino acids and the actual misincorporation events aren’t independent. I would imagine that misincorporation of chemically similar amino acids is more likely than misincorporation of dissimilar amino acids, leading to some chemical robustness against misfolding via misincorporation. This is, of course, on top of the evolution of the triplet code to allow for some chemical degeneracy between sequence-related codons.
Hi, Eric. As I understand Wilke’s theory and observations, you’re right. He links expression level to both robustness against mis-incorporation (which he further links to use of optimal codons, since he finds and theorizes that low-abundance tRNAs are more likely to be outcompeted leading to mis-incorporation), and to robustness against misfolding (tolerance of mis-incorporated amino acids). It’s a little hard to separate out which of these are theoretical, which are computer modelled, and which are observation, since they seem to blur together. But his papers are well worth a look.
[…] the past few weeks not only did I post a short update on the DRiPs hypothesis here, but coincidentally a bunch of papers on DRiPs have also been published. I’ll probably cover […]
I’ll put my money on improper protein post-translational modifications, like glycosylation, as common factor in mis-folding. These ‘tags’ are chaperone interaction sites that orchestrate timing sequence within complex folding domains (think: protein origami energetics).
See: Effect of glycosylation on protein folding: A close look at thermodynamic stabilization.
PNAS 2008. http://www.pnas.org/content/105/24/8256.abstract
Really informative iayork. Clarifying the mechanism of protein folding is essential to improve our understanding of the structure and function of proteins. Thanks ^_^