Proteins are critically important for all processes of life. For example, protein enzymes neutralize toxic substances in cells, motor proteins allow our muscles to exert force, and protein channels transmit information among neurons in the brain, among myriad other functions. Proteins are long chains in which hundreds to thousands of building blocks are arranged in a particular sequence. To carry out their biological functions, these chains must adopt precisely ordered shapes (termed structures) in a process called protein folding.
Like long strands of yarn quickly become tangled if not organized into balls, proteins that fail to adopt their functional structures in a timely fashion tend to misfold and clump together into aggregates. Many misfolded or aggregated proteins are toxic to cells. Neurons are particularly sensitive to this toxicity, and protein aggregation is associated with debilitating neurodegenerative disorders such as Alzheimer’s or Parkinson’s disease. In addition, several forms of cancer are caused by protein misfolding and aggregation.
Why some proteins robustly fold into their functional shapes whereas others misfold is not understood. Similarly, what structures are formed when folding goes awry and why they are toxic to cells is largely unclear. Our research investigates how proteins fold correctly, and how misfolding is avoided.
Most proteins require assistance to fold and to retain their normal folded structures throughout their lifetime. A large class of folding helpers, termed molecular chaperones, guides folding and prevents aggregation. This process of funneling the newly made chain into its functional structure begins early in a protein’s life, and the initial steps are crucial to set the protein on the right path for productive folding. Chaperones are indispensable for reliable folding, but how they guide the process remains poorly understood.
We are working to define pathways of folding and misfolding, and to determine working mechanisms of molecular chaperones. These mechanistic insights can open new avenues for therapeutic intervention in misfolding diseases for which there currently is no cure.