Although Arthur L. Horwich, M.D., prefers to spend as much of his time as possible in the lab, he made a happy exception on April 6, when he traveled to The Rockefeller University in New York City to accept the Wiley Prize in Biomedical Sciences. The prize is given by the Wiley Foundation, which was established in 2001 by John Wiley & Sons, a 200-year-old publisher of scientific, technical and medical books and online services.
Horwich, the Eugene Higgins Professor of Genetics and Pediatrics and a Howard Hughes Medical Institute investigator, was honored along with Franz-Ulrich Hartl, M.D., Dr.Med., of the Max Planck Institute of Biochemistry in Germany for their significant contributions to understanding how proteins fold. Scientists have long wondered how proteins make the transformation from chains of amino acids to three-dimensional structures whose specific shape determines their function. Over the last 17 years, Horwich and Hartl’s labs have helped unravel this mystery.
“In some respects it’s a recognition of our field,” says Horwich. “People are beginning to recognize that chaperone-type machines are significant and play a significant role in the cell.” Horwich and Hartl will divide a $25,000 grant, and each gave a special lecture at Rockefeller.
In 1989, building on the work of Nobel prize-winning biochemist Christian B. Anfinsen, Ph.D., who showed that folding instructions are encoded in the sequence of amino acids that make up proteins, Horwich’s lab, in a collaboration with Hartl and his postdoctoral mentor Walter Neupert, reported in the journal Nature that a specialized mitochondrial protein called Hsp60 acts as a protein-folding “machine.” Because of this protein’s helping role, it was soon dubbed a “chaperonin.” Horwich and Hartl and their colleagues then went on to elucidate the mechanism of action of the machine using the bacterial relative called GroEL.
Chaperonins are double-ringed molecules that assist in protein folding by binding unfolded proteins in an open ring and then encapsulating them under a cooperating “lid” structure (GroES) where they can fold without sticking to each other. This prevention of aggregation is an important function because such aggregates can harm the cell as in a number of neurodegenerative diseases. The two rings of a chaperonin take turns binding and folding proteins so that as one ring finishes a folding reaction, the other takes over with a new “substrate” polypeptide.
Oftentimes a protein does not fold properly with one passage into the machine and will be released from it without having reached folded form; the machine then will the bind the non-folded chain and attempt once again to correctly fold it. This process of cycling consumes cellular energy in the form of adenosine triphosphate, or atp, which binds to the machine to enable the encapsulation step and then hydrolyzes thereafter, allowing release of polypeptide.
“Art’s work has beautifully demonstrated that the notion that all proteins can fold unassisted is simply wrong. In fact, emerging evidence from his lab suggests that in the absence of the protein-folding machines he has discovered and characterized, cellular life is impossible,” says Richard P. Lifton, M.D., Ph.D., chair and Sterling Professor of Genetics and professor of medicine and molecular biophysics and biochemistry. “His work has truly revolutionized our understanding of the most fundamental aspects of cellular physiology.”
It remains unclear why the chaperone machines are unable to prevent a number of neurodegenerative diseases in which protein misfolding occurs, like Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, and mad cow disease, and these days Horwich has turned his attention to such diseases. In one approach, his group is seeking to elucidate the structure of fibrillar aggregates formed in one such disease, so-called amyloid. He is also working on a model of amyotrophic lateral sclerosis, a paralyzing movement disorder, known also as Lou Gehrig’s disease, which is in some cases caused by misfolding of a specific enzyme, superoxide dismutase. Work in microscopic nematode worms has shown that misfolding of this particular protein causes a paralyzing disorder in them as well.
Horwich and Hartl have also won the 2004 International Award from Canada’s Gairdner Foundation, which recognizes outstanding achievements in biomedical research, and the 2006 Stein and Moore Award from The Protein Society. Horwich was elected to the National Academy of Sciences in 2003 and was named a fellow of the American Association for the Advancement of Science last year.
Horwich has been a member of the medical school faculty since 1984, when he joined as an assistant professor of genetics. Now, as a full professor in the same department, he works as a bi-coastal scientist, splitting his time between New Haven and the Scripps Research Institute in La Jolla, Ca. He holds an A.B. and M.D. from Brown University and completed his residency and internship in pediatrics at Yale-New Haven Hospital.