The critical role of co-translational folding: An evolutionary and biophysical perspective

Many proteins begin to fold as they are being synthesized by the ribosome. Growing experimental evidence, supported by new theory, simulation and bioinformatics studies, suggests that many proteins rely on co-translational folding in order to fold efficiently and to avoid misfolded intermediates that arise posttranslationally. Consistent with these findings, complementary bioinformatics analyses have revealed widespread evolutionary selection for efficient co-translational folding kinetics. This perspective summarizes recent theoretical and experimental advances that have uncovered specific molecular mechanisms underlying the benefits of co-translational folding in vivo. We highlight studies involving single-domain proteins that begin adopting nativelike structure on the ribosome, which can help commit misfolding-prone domains to their native state. We emphasize the need for new experimental techniques to probe the molecular details underlying this process systematically.