Protein folding begins during synthesis and is modulated by molecular chaperones that engage the nascent polypeptide. Although the cellular environment critically contributes to the efficiency of protein maturation, little is known about how proteins fold during authentic biogenesis reactions. We are using biochemical reconstitution and structural proteomics (hydrogen/deuterium exchange- and crosslinking-mass spectrometry) to define cotranslational folding and assembly pathways on the ribosome, and in association with chaperones. Our data reveal how translation modulates protein folding, revealing pathways distinct from refolding in isolation and suggesting general principles by which the ribosome may promote folding and assembly.

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