This review summarizes a field that has recently emerged within the major area of protein structure, function, and folding. People are interested because the findings are counter-intuitive: most people think of proteins being structured if they are to perform a function.

The paper summarizes the contributions of a number of groups to this emerging way of thinking about proteins.

Proteins do not have rigid molecular structures. On the contrary, nature makes use of motion and plasticity in the structure of proteins to achieve a far greater range of functions than would be possible with static structures. Parts of some proteins are found to be completely unfolded in their functional form. We have tried to understand what benefits the lack of intrinsic structure might confer, for example, in allowing the same part of the protein to interact with different partners.

We became interested in this research through more conventional studies of protein structure and folding. Over the years, we noticed many examples of proteins where motion and flexibility were present in the active sites, i.e., the most important parts of the molecule were frequently the most mobile. The example that forced us to realize that proteins can be functional even if completely unfolded was a study we began in 1995 with a postdoctoral fellow, Richard Kriwacki. We were interested in the structure of an important component of the cell cycle machinery, the p21 cyclin-dependent kinase (Cdk) inhibitor. Rich cloned and expressed the p21 protein for analysis by nuclear magnetic resonance. Despite all of his best efforts, he was unable to induce the p21 protein to fold in order to obtain data for a structure determination. Only when he obtained a precious few milligrams of the natural partner protein Cdk2 did the mystery become clear: upon addition of Cdk2, p21 became folded. In retrospect, this makes sense: p21 must interact with a number of Cdks, so having an extremely plastic (unfolded) structure will be conducive to that function.

In the broad societal sense, I doubt that this research will have much impact, except perhaps as an example where the thinking of scientists has been channeled by the tools available for them to use. When new tools became available—in this case, the availability of gene sequences and genomes—new ways of thinking are possible.