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.

The experiments of Hartl and Horwich from 1987 to 1997 created a coherent picture of the physiologic and biophysical processes that cells use to fold proteins. In an extraordinary body of work between 1991 and 1994, Hartl defined, resolved, and reconstituted the complete pathway by which molecular chaperones cooperate to fold proteins.

Electron microscopy images of GroEL, taken by Hartl and Wolfgang Baumeister, offered the first indication that folding occurs within the GroEL cavity, a hypothesis that was proposed in 1993 by Horwich.  Hartl proposed that the chain folds in the internal microenvironment provided by the cavity of GroEL and its lid-shaped cofactor GroES.  In essence, a series of ATP-driven conformational steps change the shape of the wall of the chamber to accept an unfolded domain and then closes the chamber to reinforce the folding event.

In 1994, together with the late Paul Sigler, Horwich solved the atomic structure of GroEL, which was one of the largest protein complexes whose structure was solved at the time.  An elegant analysis using mutant GroEL proteins then confirmed, on a structural basis, that an unfolded protein binds in the centre of the hollow cylindrical GroEL complex by hydrophobic binding regions on the GroEL domains facing the central cavity.

More details followed in 1997, when Horwich and Sigler solved the atomic structure of the GroEL-GroES complex.  The structure confirmed that the inner cavity of GroEL undergoes a massive conformational change upon GroES binding. This change results in the burial of the hydrophobic regions and formation of a large hydrophilic chamber in which proteins up to about 60,000 daltons in size are free to fold. This structure also identified the mechanism of ATP hydrolysis, allowing the Horwich laboratory to work out the reaction cycle.

Folding chaperones are essential to normal life.  Elimination of chaperones from the cell causes irreversible and lethal damage because fully 10% of all the cell’s proteins require GroEL for proper folding.  Now that we know what chaperones do and can reproduce the process in the test tube, it has become possible to examine the role of the chaperones in guiding the folding of mutant proteins or in disease states. The next frontier will be to apply our knowledge of protein folding in the cell to control the process when it goes bad in diseases.

A new field of ‘‘proteostasis’’ seeks to understand the balance of protein folding, misfolding, and protein degradation that govern normal and abnormal cell physiology.  Drugs that target the folding process and that stabilize a proper folded state for misfolded proteins, such as mutant forms of CFTR (Cystic Fibrosis Transmembrane Conductance) in cystic fibrosis, show promise in the treatment of a variety of genetic diseases. Similarly, the misfolded amyloid peptide that characterizes Alzheimer’s Disease could be a target of drug therapy to prevent amyloid peptide aggregation.  If we are able to harness our understanding of protein chaperones in the treatment of diseases of protein folding, it will be because of the pioneering efforts of Hartl, Horwich, and others who elevated the field to its current level of molecular precision.


Life Science and Medicine Selection Committee
The Shaw Prize


17 September 2012, Hong Kong