Scientist joins a most distinguished fold

The elegant vaulted ceilings and leaded glass of the school’s Medical Historical Library provided the proper setting for a September 12 reception that itself marked a milestone in Yale’s medical history. Earlier that day, Arthur Horwich, M.D., Sterling Professor of Genetics and Pediatrics, learned that he was one of this year’s recipients of the Albert Lasker Basic Medical Research Award, one of the most prestigious prizes in biomedicine, for his seminal work showing how proteins attain the myriad distinctive shapes required to properly perform their functions.

The library quickly filled with well-wishing colleagues and friends—they are one and the same, judging by the many mentions made that day of Horwich’s modesty and good humor. As Dean Robert J. Alpern, M.D., noted in his remarks, we are accustomed to wondering why bad things happen to good people, but the recognition of Horwich’s research with the Lasker Award shows that “really good things can happen to nice people”: “I think everyone here knows that there’s no one nicer than Art Horwich,” said Alpern, “and probably no one more committed to their research.”

Fittingly, Horwich shares the prize with yet another friend, Franz-Ulrich Hartl, M.D., Dr.Med., of the Max Planck Institute of Biochemistry in Germany. For more than two decades, Horwich and Hartl’s transatlantic research collaboration has revealed and characterized the molecular machines that ensure that proteins fold properly, a process basic to life. The award was presented at a ceremony in New York City on September 23.

It could be said that Horwich’s path to the Lasker began when he decided to specialize in pediatrics after receiving his M.D. at Brown University, because the discoveries that decisively steered his scientific career at Yale were made while he was attempting to decipher the causes of X-linked inherited lethal ammonia intoxication, a deadly genetic disease of infancy caused by the absence of a protein known as OTC.

For OTC molecules to perform their crucial enzymatic function in the cell after they are synthesized, they must unfold, cross through the walls of compartments called mitochondria, and promptly refold into the proper three-dimensional shape.

In work that won a Nobel Prize in 1972, biochemist Christian Anfinsen, Ph.D., had shown that unfolded proteins contain sufficient information in themselves to assume a proper shape. But in 1987, experiments with OTC in yeast cells prompted Horwich and his student Ming Cheng to contemplate the then-heretical notion that there might also be molecular machines that assist proteins in folding.

Horwich and Cheng had identified a mutant yeast strain in which OTC molecules remained unfolded in the mitochondria and had stuck together in clumps (this sort of protein aggregation is a hallmark of neurodegenerative conditions such as Alzheimer’s disease) and they enlisted Hartl’s help to understand the finding. The scientists soon concluded that a defective ring-shaped protein, now known as Hsp60, was the cause.

Horwich continued his research, shifting his focus to a bacterial relative of Hsp60 called GroEL. By 1993, through collaborative work with the late Yale X-ray crystallographer Paul B Sigler, Ph.D., and numerous other colleagues, the atomic structure of GroEL—a “beautiful work of nature,” in Horwich’s words—had been revealed.

GroEL was eventually understood to be part of a pinecone-shaped complex, dubbed a “chaperonin” for its helping role, in which two stacked rings form a cylindrical chamber that can be covered by a cap, called GroES (see illustration below).

In further experiments, the purpose of those parts was clarified, and the several steps of GroEL/GroES-assisted protein folding were described down to the second.

In brief, an unfolded or poorly folded protein enters the GroEL chamber, which is then capped by GroES. This provides an opportunity for the protein to fold in isolation, protected from sticking to other proteins. After about 10 seconds the GroES cap springs off. If the protein is properly folded, it goes on to do its job; if not, it may reenter GroEL several times for additional folding attempts.

Ultimately, these findings build on Anfinsen’s work, which was done in a cell-free system, rather than overturn it. Proteins indeed contain all the information they need to properly fold, but in the cell’s crowded confines chaperonins assist the process greatly by providing a vital check on protein aggregation.

Understanding the workings of the GroEL/GroES complex has major implications for medicine, as eloquently expressed on the Lasker Foundation’s website: “When proteins aggregate, illnesses such as Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis can arise, and adjusting chaperone activity might provide therapeutic benefit ... Across the tree of life, the folding machines isolate young proteins and create a transformative moment. Then the devices send forth the mature molecules to join the hustle and bustle that makes cells what they are.”