ASCB has selected F. Ulrich Hartl of the Max Planck Institute of Biochemistry and Arthur Horwich of the Yale School of Medicine/HHMI to receive its prestigious 2017 E.B. Wilson Medal. Hartl, a biochemist, and Horwich, a geneticist, are pioneers in the realm of cellular protein chemistry whose collaborations helped unravel the molecular machinery that assists with protein folding. In his nomination letter, Alexander Varshavsky of the California Institute of Technology remarked that prior to the work of Hartl and Horwich in the late 1980s, the complexity of protein folding was greatly underestimated. Hartl and Horwich challenged the widely held notion put forth by Nobel Prize winner Christian Anfinsen that proteins fold spontaneously in cells, just as they do in test tubes.
The Centrality of Protein Folding
“The previously obscure process of protein-assisted protein folding … is now one of the most beautiful and most important chapters in molecular biology,” Varshavsky wrote. “It is difficult to overstate the centrality of protein folding and its perturbation in the etiology of major diseases, including neurodegenerative
The E.B. Wilson Awards will be presented Tuesday, December 5 at 3:15 pm, when Hartl and Horwich will give independent lectures at the 2017 ASCB|EMBO meeting in Philadelphia. Hartl has been a member of ASCB since 2004; Horwich has been with ASCB since 1991.
Hartl directs the Max Planck Institute of Biochemistry, where he has worked since 1997. Hartl’s research focuses on understanding the role of molecular chaperones in protein folding and in neurodegenerative disorders such as Huntington’s or Parkinson’s disease, which are associated with protein misfolding and cytotoxic aggregation. He investigates the chaperones and heat shock proteins (Hsp) found in yeast and mammalian cells (as well as their Escherichia coli homologs) using structural, biochemical, and cell biological methods.
“We have conducted a systematic analysis, by quantitative proteomics, to understand how the cellular proteome utilizes the chaperone network for folding and conformational maintenance,” he said. Via the molecular chaperones, Hartl explains, there is the potential for developing novel therapies.
“We have discovered that the Hsp70 system in particular, but also the TRiC chaperonin, can prevent the formation of cytotoxic aggregates, suggesting pharmacological chaperone activation as a possible strategy to combat age-dependent neurodegeneration,” he said. “We have provided evidence, in collaboration with Erich Wanker from Berlin, that such activation can be achieved, in principle, with an experimental small molecule drug [called] geldanamycin. We wish to understand why cellular chaperone capacity declines during aging and how the system can be reset to a more youthful state.”
Hartl grew up in the northern part of the Black Forest in Germany in a household that fostered free play and informal scientific exploration. Although he earned a degree in medicine from Heidelberg University he never practiced, choosing instead to devote himself fully to research. While at Heidelberg, he was inspired by the work of Wilhelm Just who was investigating the hotly debated biogenesis of peroxisomes. Hartl’s doctoral thesis, which described how the peroxisomal system can be induced to grow and take up additional proteins from the cytosol, impressed Walter Neupert, a biochemist at Munich University, who offered him a postdoctoral position. In Munich, Hartl turned his attention to the biogenesis of mitochondria and began to work on solving problems related to protein folding.
A Research Dilemma
It was around this same time that Horwich was launching his academic career as a junior faculty member in genetics at Yale. Horwich grew up near Chicago, IL, and graduated from Brown University in a unique program that combined undergraduate liberal arts with a medical degree. Although Horwich completed a medical internship and residency at Yale and worked as an attending physician in genetics for 20 years, his major focus was always on basic research. While studying a mutant strain of yeast, Horwich said he found himself in a research dilemma that became a pivotal point in his career.
“Here we were asking a somewhat new question: whether ‘de novo’ protein folding, to the properly folded ‘native’ state could be assisted by a molecular ‘machine’— a pretty radical question for the time,” Horwich said. “When we found a mutant (mitochondrial import function 4 or mif4) that behaved exactly that way, that is, proteins imported into mitochondria OK but then failed to reach active form, we were shocked. [We were] basically challenging Anfinsen’s theory that a polypeptide can fold on its own… and so we had no idea how to proceed,” Horwich said.
Hartl and his mentor Neupert heard about Horwich’s yeast mutant, and because they had more experience with protein import into the mitochondria, they offered to help. Horwich went to visit Hartl in Munich.
“That was the start of a year’s collaboration with Ulrich that helped show that indeed, our mutant affected protein folding inside mitochondria. We worked together also to identify a branch of chaperonins that are present in the cytosol of both archaebacteria and eukaryotes.”
Combining the power of genetics and biochemistry, Horwich, Hartl, his PhD student Joachim Ostermann, and Neupert discovered the steps by which Hsp60, fueled by ATP in the mitochondria of yeast and another fungus, Neurospora crassa, worked to fold proteins into their functional shapes.
“Ulrich also was interested in the idea of a ‘pathway’ of chaperone interactions, beginning with unfolded segments of chain at the ribosome, for example, that could be recognized by Hsp70 class chaperones, but then folding of a collapsed globular species could be completed inside a ring of the Hsp60 class of chaperonin ring assemblies. He carried out some really beautiful work on that and the generality of such a pathway. [I am] not sure we could ever have convinced anyone of the existence of a folding machine without the collaboration with Ulrich and Walter. Their phone call was a gift out of the blue.”
Confirm and Support
Following their collaboration, which resulted in two seminal papers in 1989, Horwich and Hartl returned to their own research endeavors. Hartl worked with Bill Wickner at the University of California, Los Angeles, and later became a tenured professor at Sloan Kettering Cancer Center before finally moving back to Germany and to the Max Planck Institutes. Today, Horwich is the Sterling Professor of Genetics and Pediatrics at Yale School of Medicine and an HHMI investigator. Over the years, however, they found that their work continued to confirm and support one another. “There were points where our findings came at similar times and agreed, such as the finding that polypeptides are folded inside the encapsulated chaperonin ring,” Horwich said.
For his talk in December, Horwich said he plans to discuss the structure and mechanisms related to the chaperonin ring machines. Using a mouse model, his work is beginning to elucidate a mechanistic understanding of a form of amyotrophic lateral sclerosis that is caused by protein misfolding.
Hartl’s talk will be complementary. “Much work still lies ahead, but we are optimistic that the basic research toward understanding the cellular machinery of protein folding and quality control will eventually contribute to solving some of the most pressing medical problems of our aging population,” Hartl said.
About the Author:
Mary Spiro is ASCB's Strategic Communications Manager.