Pervasive fold switching in a ubiquitous protein superfamily

Porter, Lauren L.; Kim, Allen K.; Looger, Loren L.; Majumdar, Anaya; Starich, Mary

Fold-switching proteins challenge the one-sequence-one-structure paradigm by adopting multiple stable folds. Nevertheless, it is uncertain whether fold switchers are naturally pervasive or rare exceptions to the well-established rule. To address this question, we developed a predictive method and applied it to the NusG superfamily of >15,000 transcription factors. We estimate that a substantial population (25%) of the proteins in this family switch folds. Circular dichroism and nuclear magnetic resonance spectroscopies of 10 sequence-diverse variants confirmed our predictions. Subsequently, we leveraged family-wide predictions to determine both conserved contacts and taxonomic distributions of fold-switching proteins. Our results indicate that fold switching is pervasive in the NusG superfamily and that the one-sequence-one-structure protein folding paradigm significantly biases protein structure prediction strategies.