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Protein folding in the cell: an inside story

Nature Medicine volume 17, pages 1211–1216 (2011)Cite this article

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The final step of information transfer from DNA to effector protein involves the folding of newly translated polypeptide chains into characteristic three-dimensional active structures. In the fall of 1972, while working in a biochemistry laboratory as an undergraduate at Brown University, I heard about an astonishing experiment for which Christian Anfinsen was receiving the Nobel Prize in Chemistry. Anfinsen and his co-workers had unfolded purified RNase A by reducing its disulfide bonds and exposing it to a denaturing agent, and then asked whether the protein could find its way back to the enzymatically active native state upon removal of the reducing agent and denaturant1. Amazingly, it did. I was utterly haunted by the beauty of this observation and by the profound conclusion that the primary structure of a protein contains all the information necessary to direct its folding to the native functional state. I could never have imagined that, many years later and in a completely unexpected fashion, I would have something to add to something so fundamentally beautiful.

I finished my undergraduate and medical training at Brown and went to Yale for pediatric residency, but, by the second year of training, I was missing the laboratory. I became captivated by the problem of malignant transformation mediated by single viral genes, and, by the end of my residency, I had amassed on my nightstand a stack of several hundred papers on the topic.

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Figure 1: Mitochondrial protein import and the demonstration that a folding machine assists refolding of newly-imported proteins.
Figure 2: Cutaway views of crystallographic models of unliganded GroEL and an asymmetric GroEL-GroES-ADP7 complex.
Figure 3: The GroEL-GroES reaction cycle.

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Acknowledgements

Many of the major participants in the chaperonin work referred to above are pictured in the illustration on p. xiii. There have been many other collaborators, both in the early work and more recently, who also contributed substantially to the understanding of this system. I regret that space limitations prevented me from referring to them here, but I want to express how deeply grateful I am to everyone with whom I've interacted. Surely, the recognition of this work is shared by all of us. But, more selfishly, it has been a pure joy for me over these past 20 years to work in the lab, at the bench, day by day and side by side with my group members, sharing our ideas, dreams, reagents, frustrations and, of course, joys of discovery as a scientific family. No one could ask for a more enjoyable life. I wish to thank the US National Institutes of Health for supporting the early phase of our work and the Howard Hughes Medical Institute (HHMI) for supporting our subsequent work. I am particularly grateful to the HHMI for allowing me to 'follow my nose' through this work, no matter how risky the undertaking. I also thank HHMI for making our work environment a paradise in which to pursue ideas and do experiments. Finally, I thank W. Fenton for his critical comments during the preparation of this manuscript.

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  1. Arthur L. Horwich is at the Yale University School of Medicine, New Haven, Connecticut, USA.,

    Arthur L Horwich

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Correspondence to Arthur L Horwich.

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Horwich, A. Protein folding in the cell: an inside story. Nat Med 17, 1211–1216 (2011). https://doi.org/10.1038/nm.2468

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