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Chaperone-assisted protein folding: the path to discovery from a personal perspective

Nature Medicine volume 17, pages 1206–1210 (2011)Cite this article

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Protein folding is the process by which newly synthesized polypeptide chains acquire the three-dimensional structures necessary for biological function. For many years, protein folding was believed to occur spontaneously, on the basis of the pioneering experiments of Christian Anfinsen, who showed in the late 1950s that purified proteins can fold on their own after removal from denaturant1. Anfinsen had discovered the fundamental principle that the linear amino acid sequence holds all the information necessary to specify a protein's three-dimensional structure. But it soon became apparent that test-tube folding experiments work mostly for small, single-domain proteins, often only in conditions far removed from those encountered in a cell. Large proteins frequently fail to reach native state under these experimental conditions, forming nonfunctional aggregates instead. Despite these problems, protein folding was of little interest to cell biologists until the mid- and late 1980s, when the chaperone story began to unfold. As a result, we now know that in cells, many (perhaps most) proteins require molecular chaperones and metabolic energy to fold efficiently and at a biologically relevant rate. Here I describe, from a personal perspective, the developments leading to this new view.

After completing my doctoral thesis at Heidelberg University in 1985, I joined the laboratory of renowned biochemist Walter Neupert at the University of Munich. Walter's group studied how cell organelles such as mitochondria import newly synthesized proteins from the cytosol. The move to Munich turned out to be crucial for both my professional and personal future—the latter because Walter allowed me to attend a molecular biology summer school on a Greek island, where I met my future wife Manajit (facilitated by the chaperone-free, Mediterranean atmosphere, I might add).

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Figure 1: Art Horwich (right) and I (left) in March 1991 taking a walk near my parents' village in the northern part of the Black Forest.
Figure 2: Averaged electron microscopic images.
Figure 3: The current model for protein folding in the GroEL-GroES chaperonin cage.
Figure 4: Model from 1993 for the pathway of chaperone-assisted protein folding in the E. coli cytosol, shown for a GroEL-dependent protein (reproduced from ref. 25).

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Acknowledgements

I had the privilege to work with many young scientists who deserve my deeply felt gratitude. I apologize to those whose contributions could not be discussed here. I am especially grateful to Manajit, my wife and colleague, who has contributed tremendously to our work and who shares my excitement for science. I thank my mentors and advisors for continued support and guidance, especially W. Neupert, as well as W. Just, H. Schimassek, W. Wickner and J. Rothman. I would also like to thank all our colleagues in New York City, especially those at Memorial Sloan-Kettering, for welcoming us so warmly into their community and making our years in the Big Apple such a fantastic experience. Finally, I would like to thank the chaperone research community for more than 20 years of collegial support and for the many friendships that have evolved. I acknowledge generous research support from the Max Planck Society, the Deutsche Forschungsgemeinschaft, the European Union, the Howard Hughes Medical Institute, the US National Institutes of Health and the Memorial Sloan-Kettering Cancer Center.

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  1. F. Ulrich Hartl is at the Max Planck Institute of Biochemistry, Martinsried, Germany.,

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Hartl, F. Chaperone-assisted protein folding: the path to discovery from a personal perspective. Nat Med 17, 1206–1210 (2011). https://doi.org/10.1038/nm.2467

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