March 2013

Hartl, Horwich share Tabor Research Award for work with chaperone proteins

F. Ulrich Hartl and Arthur Horwich

“ We are deeply honored to receive this award named after Herbert Tabor, a scientist and colleague we so highly respect. It is wonderful that our work on chaperone-assisted protein folding is recognized by the large community of biochemists and molecular biologists represented by ASBMB.”

F. Ulrich Hartl of the Max Planck Institute for Biochemistry and Arthur Horwich of the Yale School of Medicine have won the American Society for Biochemistry and Molecular Biology’s Herbert Tabor Research Award for pioneering work in the field of protein folding.

This award is given for excellence in biological chemistry and molecular biology research in honor of the many contributions of Tabor to both the ASBMB and the Journal of Biological Chemistry, for which he served as editor for more than four decades.

Hartl and Horwich identified and characterized a group of proteins known as chaperones, which are molecular machines that aid the process of protein folding. “These machines and their mechanics were illuminated primarily through the pioneering work by the Hartl and Horwich laboratories,” Alexander Varshavsky explained in nominating the pair for the award. “Their contributions are numerous, crucial and profoundly complementary. Moreover, some of their most important early discoveries stemmed from their direct collaboration.”

The discovery of chaperone-assisted protein folding began while Horwich was a young independent investigator at Yale University studying the machinery that imports proteins, which are imported in an unfolded state, into the mitochondria. Horwich identified a mutant where a target protein was imported properly but remained unfolded. Horwich teamed up with Hartl, an expert in mitochondrial import biochemistry who was then at the University of Munich, and they determined that the mutant lacked a protein called Hsp60. Together, they demonstrated that Hsp60 was a multisubunit 14-mer molecular machine that aided the process of protein folding in an ATP-dependent manner. They later jointly determined that Hsp60 also prevents protein aggregation by binding pre-existing proteins that are unfolded due to stress.

Although Hartl and Horwich continued to investigate the chaperones independently, their laboratories, using different but complementary methodologies, uncovered the reaction cycle for the Hsp60 homolog in prokaryotes, GroEL-GroES. Using biochemical and structural studies, they determined that the unfolded polypeptide first binds to GroEL and then undergoes a complex reaction. First, the GroES subunit displaces the unfolded polypeptide from its initial GroEL binding sites, which sequesters the unfolded polypeptide in a central cavity in GroEL. Here, the protein remains encapsulated and free to fold, unimpaired by aggregation. ATP hydrolysis in the folding-active ring followed by ATP binding to the opposite ring of GroEL then induces release of both GroES and the polypeptide. Substrate that has not yet folded to completion rebinds to GroEL for another folding attempt.

It is now understood that there are two classes of chaperones, the Hsp70/DnaK family and the Hsp60/GroES–GroEL family (also known as chaperonins).

Hartl and his team found that protein folding utilizes both classes of chaperones. For example, in bacteria DnaK stabilizes unfolded polypeptides, promotes the folding of some and transfers others to GroEL. Hartl researched the types of unfolded polypeptides that interact with GroEL and found that they often have complex alpha/beta domain topologies, such as the TIM barrel fold. Additionally, in eukaryotes, proteins with multiple domains benefited from sequential and co-translational folding by Hsp70 and other chaperones, including the eukaryotic homolog of GroEL. Hartl also has studied how the Hsp70 family of proteins prevents the aggregation of proteins, specifically the toxic polyglutamine protein aggregates that are the hallmarks of neurodegenerative disease.

Horwich, in collaboration with the late Paul Sigler, determined the crystal structures of GroEL and the GroEL–GroES complex. They found that GroEL consists of three domains, a large equatorial domain that contains the ATP-binding pocket, an apical domain that forms the opening of the central GroEL channel and is thought to bind unfolded proteins and GroES, and an intermediate domain that connects the equatorial and apical domains. These structural studies, in addition to helping to elucidate the chaperone reaction cycle described above, revealed the major conformational changes that accompany chaperone-mediated protein folding.

Varshavsky said, “Owing to the work by these nominees, the previously obscure process of protein-assisted protein folding — its complexity was underestimated by early researchers — is now one of the most beautiful and important chapters of the contemporary molecular biology.”

Both of the winners have received multiple awards for their work. They shared the 2011 Albert Lasker Basic Medical Research Award, the Shaw Prize in Life Science and Medicine in 2012, the Louisa Gross Horwitz Prize for Biology or Biochemistry in 2008, and the Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science and the Wiley Prize in Biomedical Science, both in 2007. Horwich, a Howard Hughes Medical Institute investigator, has been a member of the National Academy of Sciences since 2003. In 2011, Hartl was elected into the academy as a foreign associate.

Hartl and Horwich will receive their award during the Experimental Biology 2013 conference in Boston, where they will deliver award lectures. The presentation will take place at 6 p.m. April 20 in the Boston Convention and Exposition Center.

Sarah GoodwinSarah Goodwin ( earned her Ph.D. in cell biology at the University of California, San Francisco, and is now director of the iBioSeminars project (

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