Silently Shaping Structure- Exploring the role of synonymous genetic coding in shaping the local protein backbone structure
In the mid-20th century Christian Anfinsen, later Nobel Prize winner, showed that RNaseA can be denatured to lose structure and function and then subsequently renatured to regain both, setting the bedrock of our understanding of what governs protein folding. His experiments suggested that proteins carry no memory of the genetic sequence from which they were translated, despite 18 out of the 20 amino acids being translated from non-unique, synonymous, codons. Subsequently, genetic alterations leaving the amino acid sequence unchanged were termed and largely considered `silent`. Later findings demonstrated that synonymous mutations can alter translation speeds and accuracy affecting co-translational folding and the overall, globular, structure of the resultant protein. We have recently shown that synonymous codon usage is associated with the local structure (backbone dihedral angle distribution) of the translated amino acid. However, these computational results are unable to establish causality; the association may be evolutionary, or an active translation-dependent effect. The goal of this project is to explore the latter; can synonymous mutations alter the local structure of the encoded amino acids? We are exploring this hypothesis by targeting proteins that on one hand give high-resolution X-ray diffraction patterns and on the other hand contain short noninteracting sequences whose initial (codon- sensitive) structure should be minimally affected by protein folding.
