To carry out biological functions, a protein must fold into a complex structure encoded by its amino-acid sequence. When this sequence is changed, for example by DNA mutations or errors in protein synthesis, the protein may misfold, not only losing its function but becoming a toxic, aggregation-prone rogue.
Protein misfolding profoundly shapes organism fitness (including human health): it is a cause of major human diseases, a requirement for proper immune-system function, and a dominant determinant of the fitness effects of mutations in protein-coding genes. Yet little is known about the dominant causes, amounts or consequences of protein misfolding at the scales of whole genomes and organisms. What fraction of newly synthesized proteins misfold? Are some classes of proteins exceptionally robust to mistranslation? If so, what phenotypic consequences result from compromising that robustness?
We are exploring the scope, scale and causes of protein misfolding and its effects on organism fitness, with a strong focus on newly synthesized proteins. Using the yeast Saccharomyces cerevisiae as a model system, our research combines evolutionary genomics, which reveals broad patterns of fitness imprinted in DNA, with system- and molecule-level misfolding studies designed to illuminate the conserved biochemistry underlying these patterns.