Biochemistry Seminar

Combining multiple domains into a single polypeptide is a common evolutionary strategy to generate proteins with novel functions. How these long polypeptides fold into functional structures without forming toxic misfolds or aggregates remains poorly understood. Folding of multi-domain proteins is inextricably linked to protein synthesis and interactions with cellular machinery. We are employing single-molecule manipulation with optical tweezers and live-cell experiments to dissect folding pathways and define contributions from cellular machinery. We find that chaperone interactions not only reduce misfolding among unstructured domains, but also shield already folded domains from destabilizing interactions, a novel aspect of nascent chain-binding chaperone function. Throughout synthesis, the nascent protein interacts with the ribosome. These interactions generally compete with either folding of misfolding, depending on nascent chain length. However, specific interactions can also stabilize folded structures that serve as intermediates on the path to the native protein. Collectively, our studies shed light on co-translational folding of multi-domain proteins and may be a first step toward defining a "folding code" for newly synthesized proteins.

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