Integrative structural biology of protein folding during biosynthesis on the ribosome

The ribosome is the molecular machine that manufactures proteins from information encoded in our DNA in all cells. Proteins are synthesised as a chain of amino acids built one at a time and must acquire (or fold) their particular shape for them to function. Failure to fold (misfolding) can have devastating consequences, and is implicated in many diseases including neurodegeneration and some cancers. During protein synthesis, the ribosome appears to have a key role in guiding folding of nascent proteins before they are released into the cell’s environment. Despite a wealth of information on the ribosome’s ability to form peptides, the understanding of the protein folding processes on the ribosome remains sparse.

We aim to transform this understanding by applying recently developed genetic engineering methods to capture different stages of protein synthesis on the ribosome. Together with atomic-level visualisation methods we will analyse this series of 3D snapshots to describe how the ribosome guides nascent protein folding. This has important ramifications for understanding why folding can fail and how this is dealt with by the cell. Armed with this information, we can then design ways to manipulate the process, for example using novel antibiotics and antibodies, to target the nascent protein or ribosome to reconfigure protein folding and avoiding misfolds.