for their contributions to the understanding of the molecular mechanism of protein folding. Proper protein folding is essential for many cellular functions.
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.
Protein molecules are long, complex strings of amino acids that have many possible ways of folding into a compact shape, yet they somehow fold beautifully in the crowded interior environment of a cell. Folding is guided by the sequence of amino acids in a protein but sometimes this process goes bad when proteins are changed because of mutation or when surfaces that are incompatible with the water environment of the cell cytoplasm become exposed during the folding process. Cells have evolved molecular chaperones, such as GroEL, to help shield such surfaces and to provide a protected environment in which to complete the folding process. The surfaces of this remarkable machinery are very forgiving. They actually utilize metabolic energy (i.e., ATP hydrolysis) to alternate their physical chemistry between hydrophobic states and hydrophilic states, which restarts the folding when it stalls and expels the protein when folding is completed. In the case of GroEL, a molecular chaperone shaped like a test tube, access to the cavity is highly selective and limited to only newly-made proteins or those purposely unfolded to repair damage or mistakes.
The 2012 Shaw Prize in Life Science and Medicine is awarded to Ulrich Hartl, Director, Max Planck Institute of Biochemistry in Martisried, Germany and Arthur Horwich, Professor of Genetics and Investigator of the Howard Hughes Medical Institute, Yale University School of Medicine. Together, these two investigators identified the chaperones and their mechanism of action in the cell powerhouse, the mitochondrion, and in the cell sap, the cytoplasm.
Franz-Ulrich Hartl was born in 1957 in Essen, Germany. He currently holds the position of Director, Max Planck Institute of Biochemistry in Martinsried, Germany. Hartl received his MD from the University of Heidelberg in 1982 and did postgraduate work at Heidelberg, Munich and then Los Angeles from 1982 to 1990 before he began his independent work as a faculty member at the Sloan Kettering Research Institute where he remained from 1991 to 1997. During that time he held the position of Howard Hughes Investigator from 1994 to 1997 after which he returned to Germany to assume his current position. In addition to numerous prizes, including the Albert Lasker Award in Basic Medical Research, which he shared with Arthur L Horwich in 2011, and election to honorific societies, Hartl was elected as a Foreign Associate of the United States National Academy of Sciences in 2011.
Arthur L Horwich was born in Chicago, USA in 1951. He currently holds the position of Professor of Genetics at the Yale University School of Medicine and Investigator of the Howard Hughes Medical Institute. He received his undergraduate and medical training at Brown University from 1969 to 1973. After a period of postgraduate clinical training in pediatrics at Yale, Horwich devoted himself to a basic science career as a postdoctoral fellow at the Salk Institute (1978 – 1981) and then back at Yale (1981 – 1984). He has remained on the Yale faculty since that time. In addition to numerous prizes, including the Lasker Award in Basic Medical Science, which he shared with Franz-Ulrich Hartl in 2011, Horwich was elected to the United States National Academy of Sciences in 2003.
