Yale Investigator Receives Wiley Prize for Pivotal Discovery

Arthur Horwich, M.D., a Yale School of Medicine researcher who has dissected the mechanism of a molecular machine that mediates protein folding in the cell, has been awarded the Wiley Prize in the Biomedical Sciences for his groundbreaking research.

Horwich, the Eugene Higgins Professor of Genetics and Pediatrics and investigator of the Howard Hughes Medical Institute, will receive $25,000, which will allow him to continue researching a vital component of the living world, proteins. His work describes the mechanism of action of a machine that carries out the folding of newly-made proteins in the cell, preventing them from misfolding. As Horwich explains, “Faulty protein folding can lead to an aggregation of misfolded proteins, for example, forming fibrillar tangles in the brain in such diseases as Alzheimer’s and Parkinson’s.”

He discovered that folding is assisted by large ring-shaped machines, appropriately called chaperonins, that smooth the folding process, preventing wrongful interactions that led to aggregation, much like chaperones at a social event. The chaperonin, he said, is “an editing machine” that uses the energy of adenosine triphosphate (ATP) to edit the conformational state of proteins so that they get to the correct functional so-called “native state.” Horwich said this activity is particularly needed under conditions in the cells, where there is a relatively high temperature and where there is a dense crowd of macromolecules.

Horwich first heard about protein folding 35 years ago as a college student at Brown when Christian Anfinsen, a scientist with the National Institutes of Health, received a Nobel Prize in Chemistry for his discovery that all of the information needed for a protein to fold correctly was located within its own primary sequence of amino acid building blocks. For many years, it was assumed that proteins must likewise spontaneously fold to their native state inside living cells.

As a junior faculty member in genetics at Yale, Horwich accidentally stumbled into an activity in mitochondria that was required for the proper folding of the proteins coming into these organelles. He observed misfolded proteins aggregating in yeast mitochondria, which indicated that in cells many proteins require assistance to fold properly.

Horwich’s group has spent the past 15 years investigating the activity they discovered. They learned that a large double donut-shaped machine is responsible. They analyzed how that machine uses the energy of ATP and a lid structure to mediate folding inside a cavity within the ring. They found that an unfolded protein binds within an open ring of the machine and then the lid structure encapsulates it. The protein then folds in the sequestered space inside the cavity. The protein, through the action of ATP, pops out in its folded form in a sort of jack-in-the-box mechanism.

“Art showed that the idea that all proteins fold unassisted was wrong and that many proteins require outside help,” said Richard Lifton, M.D., professor and chair of the Department of Genetics. “This is the work of a brilliant and passionate scientist who has followed a problem from its initial discovery to a detailed picture of how this novel machine works to grasping an understanding of the implications for human disease.”

According to Lifton, Horwich’s simple genetics experiment asked why a particular genetically defective yeast mitochondria failed to function properly, or why the proteins entering them misfolded. He answered the question using what Lifton calls “elegant genetics” by proving with co-awardee Ulrich Hartl that the chaperonin binds the imported proteins in the ring-like structures to aid in their folding.

Both Lifton and Horwich agreed that without a place like Yale, this type of innovation could not be carried out. “There is space for fantastic basic science from top to bottom here,” Lifton said. Additionally, the collaborative spirit that captures the sciences at the University enable these cutting-edge experiments to follow through to a successful completion, Horwich said.

Horwich was elected to the national Academy of Sciences in 2003, was recipient of the prestigious Gairdner International Award for achievement the following year, and, most recently, received the 2006 Stein and Moore Award of the Protein Society.

Horwich has been a member of the Yale 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.

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