NIH Research Festival
FARE Award Winner
Synonymous mutations and mRNA specific structures can modulate the rate of translation, which can substantially affect protein folding. Using the available protein structures from two Eukaryotes and three Prokaryotes, we explored the potential impact of mRNA structure, which was inferred from the mRNA folding energy (dG) profile, on the structure of the encoded protein. We show that dG is positively correlated with several descriptors of protein compactness in Prokaryotes. mRNAs with stable structures that slow down translation typically encode compact proteins. The same relationship was observed in Eukaryotes only after controlling for the GC content, showing that the latter is a suppressor variable. Disordered parts of protein, which are more common in Eukaryotes, are mainly composed of polar residues, which are preferentially encoded by rich GC codons. We further analyzed the relationship between protein structure and mRNA folding energy and found that the size and solvent accessibility of ordered parts of protein positively correlates with the local mRNA folding energy, whereas no such correlation is observed in disordered parts of protein. Thus, there appears to be a robust local relationship between the mRNA folding energy profile and folded portions of a protein. The mRNA structure appears to act as a protein folding controlling device by reducing ribosome speed when the nascent peptide needs time to form and optimize the core structure. This conclusion is compatible with the results of previous studies which indicate that increasing translation speed leads to protein misfolding.
Scientific Focus Area: Computational Biology
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