Protein molecules organize and catalyze most of the metabolic and growth activities of cells. Each protein begins its life as a long linear chain of amino acids whose chemical properties and interactions dictate the final folded shape and functional qualities of enzymes and structures within all biological cells. Some proteins fold spontaneously in the test tube, yet others require protein “chaperones” to guide folding in intact cells and in the test tube. Beginning in 1989, Franz-Ulrich Hartl and Arthur L Horwich, first as a team and then in their own laboratories, identified the chaperones that mediate protein folding in the cell powerhouse, the mitochondrion, and in the cell sap, the cytoplasm.

Hartl and Horwich began their studies with a yeast mutant deficient in folding single and multisubunit proteins in mitochondria. They demonstrated the action of a chaperone, called GroE, in the test tube and later through detailed inspection using high-resolution structure analysis where the exact geometry of the folding chamber could be visualized atom-by-atom. Independently, Horwich solved the atomic structure of the folding machine in collaboration with the brilliant structural biologist, the late Paul Sigler, also of Yale. In separate contributions, Hartl and Horwich showed that GroE captures an unfolded polypeptide in a closed chamber that changes its shape in stages driven by the cell’s energy currency, ATP, until the folded protein is ejected as a finished product.

These seminal contributions on GroE, along with detailed inspection of other chaperones, help to explain what goes wrong in diseases of protein folding such as cystic fibrosis, Alzheimer’s Disease and Huntington’s Disease. As misfolded proteins can be toxic to cells and are involved in many degenerative diseases, a better understanding of protein folding will help in developing new therapeutic approaches.

Life Science and Medicine Selection Committee
The Shaw Prize

29 May 2012   Hong Kong