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Protein folding from 1961 to 1982

Nature Structural Biology volume 6, pages 814–817 (1999)Cite this article

It was 1961. Anfinsen1 had shown that the correct disulfide bonds of ribonuclease A (RNaseA) form spontaneously upon oxidation in air, driven by the free energy of folding. The central dogma of molecular biology, DNA→RNA→Proteins, was being analyzed step by step and the factors (especially enzymes) needed to make each step take place in vitro were being discovered. Anfinsen's work illuminated the point that the chemical process of RNA translation yields an unfolded polypeptide chain and the chain must fold before it becomes a biologically active protein. Previously some proteins, such as RNase A and chymotrypsinogen had been shown to denature and renature reversibly when their disulfide bonds were left intact. But how are the disulfide bonds formed? Most proteins containing disulfide bonds unfold when these bonds are reduced to the form present in the nascent polypeptide chain. Straightforward calculations had shown that the probability of forming the correct bonds in the fully unfolded state is close to zero for a protein such as RNase A, whose eight Cys residues form four disulfide bonds. In addition to demonstrating that folding drives disulfide bond formation, Anfinsen found that some incorrect disulfide bonds are formed initially but are reduced and reshuffled, provided a suitable reducing agent is present; moreover, an enzyme, protein disulfide isomerase, achieves this reshuffling in vivo2,3. Through this work, Anfinsen connected the new science of molecular biology with the established field of protein chemistry, and he focused the attention of scientists in both fields on solving the mechanism of protein folding.

In 1961 the structure of one protein, myoglobin, was known at 6 Å resolution and its 2 Å structure would soon be published. The structural determinations of hemoglobin and hen lysozyme were well under way. Regarding the energetics of folding, Kauzmann had shown in 1959 that the hydrophobic interaction would be a dominant factor, but in 1961 this was a revolutionary concept, not yet widely accepted. Schellman in 1955 and later also Klotz had shown that model structures formed in water by amide hydrogen bonds have at best marginal stability. The time was right to begin the task of isolating and characterizing folding intermediates: but did they exist?

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  1. the Department of Biochemistry, Stanford University School of Medicine, Beckman Center, Room B-400, Stanford, 94305-5307, California, USA

    Robert L. Baldwin

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Baldwin, R. Protein folding from 1961 to 1982. Nat Struct Mol Biol 6, 814–817 (1999). https://doi.org/10.1038/12268

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