Amino acid sequence control of protein folding and assembly

The amino acid sequence of a linear polypeptide chain contains the information necessary to achieve the native three-dimensional structure of a protein, though the mechanism by which this is accomplished is still not totally understood. The challenge of understanding the nature of protein grammar in terms of the final structure is of paramount interest as many disease are related to misfolding and aggregation of proteins. Using preexisting genetic variants of phage P22 coat protein which are defective in protein folding and have impaired assembly, I isolated additional amino acid substitutions that were capable of alleviating the folding and assembly defects of temperature-sensitive-folding ( tsf) mutants. I identified several different groups of second site suppressors, each of which may potentially reveal different mechanisms by which folding and assembly defects may be corrected. Interestingly, one group of amino acid substitutions, known as global suppressors, are capable of alleviating the folding defects of numerous tsf mutants. Our characterization of the mechanism by which the global suppressors alleviate the original tsf phenotype in coat protein has shown that folding defects in large oligomeric proteins can be suppressed by an increase in the rate and yield of assembly. Perhaps this could be a general mechanism utilized to correct folding defects in large multimeric proteins.