Shu-ou Shan

Assistant: Andy Lo

Research:
Generation of a functional proteome requires that nascent polypeptides fold into the correct structures, assemble with interaction partners, localize to the appropriate cellular destination, and undergo regulated quality control. In the Shan lab, we integrate the approach of mechanistic enzymology with biophysical tools, including fluorescence spectroscopy, single molecule fluorescence microscopy, NMR, EPR, and cryo-EM, to decipher the molecular basis of diverse protein biogenesis pathways.

Nascent Protein Selection and Triage at the Ribosome. During protein synthesis, numerous protein biogenesis factors bind at the polypeptide tunnel exit of the ribosome to direct the nascent protein into distinct biogenesis pathways. These include cotranslational chaperones that assist in folding and assembly, targeting and translocation machineries that couple protein synthesis to localization, and modification enzymes that regulate the maturation and quality control of proteins. A major effort of ours is to elucidate the molecular mechanism of diverse cotranslational protein biogenesis machineries and more importantly, to decipher how they coordinate in space and time to select nascent proteins into the appropriate biogenesis pathways. Ultimately, we aim to develop a comprehensive and quantitative model that can accurately explain, or even predict, what happens to a nascent protein as it emerges from the ribosome, and how genetic and environmental factors impact these decision-making processes.

Mechanism and Engineering of Molecular Chaperones. Unfolded and partially folded proteins populate the newly synthesized proteome, leading to the generation of toxic protein aggregates that underlie numerous neurodegenerative and other protein misfolding diseases. Our second major research goal is to understand how molecular chaperones in the cell protect proteins from misfolding/aggregation, guide proteins through productive folding pathways, and even "repair" misfolded and aggregated proteins. Leveraging our knowledge of the mechanism of molecular chaperones and the tools in directed evolution, we are also establishing novel directed evolution platforms to engineer improved chaperones that are tailored to aggregation-prone proteins of interest.