Mechanistic Study and Drug Development for Protein Homeostasis Diseases

Proper protein homeostasis is essential to all cells and requires the correct folding and localization. Due to the nature of amino acid sequences, environmental stress, and aging, newly synthesized proteins constantly face a risk of misfolding and aggregation in the cytosol before safely reaching their functional conformation and final destination. Cytosolic chaperones not only assist in the proper folding of soluble proteins but also fine-tune the influx of membrane proteins to their correct destination. Since protein aggregation and misfolding are toxic to the cells and are the common cause of numerous protein homeostasis diseases, molecular chaperones have been suggested as an excellent therapeutic target for those diseases.

Our research group takes an integrative approach employing sophisticated biochemistry, cell biology, and protein engineering to address the following fundamental questions: First, how do cytosolic chaperones prevent aggregation of membrane proteins and coordinate with membrane receptors to deliver their client proteins to the membrane? Second, how could a chaperone evolve into a superactive chaperone variant to efficiently prevent pathological aggregates for neurodegenerative diseases? Therefore, we specifically aim to understand the molecular mechanisms of chaperone action in regulating membrane protein biogenesis and reengineer the chaperone network to develop drugs for protein homeostasis diseases.