Integrative structural biology of protein folding during biosynthesis on the ribosome (360G-Wellcome-206409_Z_17_Z)

Central to the activity of all living systems is the need for polypeptide chains to acquire their biologically-active structures and avoid the competing events of misfolding. It is well established that the majority of proteins begin to acquire structure as highly-dynamic nascent chains during biosynthesis on the cell’s protein biosynthesis machinery, the ribosome. A detailed molecular understanding of how this native structure is acquired and how misfolding is avoided during biosynthesis is sparse. We will build on our capacity to derive structural and dynamic mechanistic information of the fundamental process of co-translational folding: we will produce a multi-scalar analysis extending from in vitro to in vivo to provide a comprehensive, high-resolution description of emerging nascent chains (NC) during biosynthesis. Our research will integrate NMR and cryo-EM to answer emerging questions regarding the observation that the ribosome itself can modulate folding processes, and also act as a hub for the recruitment and co-ordination of auxiliary proteins that can assist NC folding and modification processes. Structure-based design, incorporating protein engineering and ribosome modification will dissect NC folding mechanisms and understand how misfolding is avoided. This underpins aims to reshape co-translational folding, targeting the ribosome and NC at the earliest stages of protein-biosynthesis.