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If dogma dictates that proteins need a structure to function, then why do so many of them live in a state of disorder?
B Y TA N G U Y C H O U A R D

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eith Dunker’s life is a mess. His desk is so swamped with books, old chocolate bars, half-reviewed manuscripts, pens, diet coke bottles and — somewhere — a stray sock, that he ends up printing papers again rather than wading in to find theoriginal. “I’m so disorganized,” he crows, “some people have called me Dr Disorder.” But he remembers with great precision the moment that disorder invaded his scientific life. It was 15 November 1995, at 12:40 p.m., halfway through a seminar by crystallographer Chuck Kissinger, at Washington State University in Pullman, where Dunker was then a biochemist. Dunker was staring at a slide showing theatomic structure of calcineurin, an enzyme targeted by immunosuppressive drugs. What caught his attention wasn’t the intricate structure but something missing from it: a dotted line representing a string of amino acids with a position too variable to be determined by X-ray crystallography, as the rest of the protein had been. And Kissinger was insisting that this loop had to remain flexible forcalcineurin to serve its crucial function in the human immune system. “It hit me like a brick,” says Dunker: this wayward piece of protein flouted a century of dogma. A central tenet in molecular biology is that the function of a protein depends critically on its fixed threedimensional structure; for example, enzymes bind to specific substrates because their shapes match perfectly, as immortalized inthe ‘lock-andkey’ model proposed by chemist Emil Fischer as early as 1894. But this part of calcineurin seemed to disobey these rules, by providing function without structure. Now Dunker was wondering how many other proteins were ignoring the rules too. To find out, he and his colleagues wrote a bioinformatics program that predicted which protein segments are ‘intrinsically disordered’ — meaningthat they do not fold spontaneously into a unique three-dimensional shape. Today, this NATURE.COM and other similar programs predict that about Read about protein 40% of all human proteins contain at least one folding that can intrinsically disordered segment of 30 amino cause disease: acids or more, and that some 25% are likely to be go.nature.com/s6w5mm

disordered from beginning to end1. Thispart of the protein universe had largely been ignored because disordered protein segments impede crystal formation — a prerequisite for X-ray diffraction, the predominant way structures are deduced — and structural biologists clip them out whenever they can. Today, though, “the recognition of disorder has grown dramatically”, Peter Wright, a protein biophysicist at the Scripps Research Institutein La Jolla, California, told the American Association for the Advancement of Science meeting in Washington DC last month. A large part of that recognition has come from studies using nuclear magnetic resonance (NMR) spectroscopy, which allows researchers to determine the structures of small proteins even as they twist and turn in solution. Such work has shown that disorder can actually beessential to function by helping a signalling protein to recognize and react to a protein partner, or by allowing a regulatory protein to interact with multiple targets. Still, says Wright, “that hasn’t got through to the textbooks”. Many structural biologists see no need for revision. “My mantra has been: function requires structure,” declares Tom Steitz, a crystallographer at Yale University in NewHaven, Connecticut. “Some flexibility can be required, it may be an essential part of the assembly process, but it’s not interesting until the proteins get to do their job.” Critics argue that the computer programs predicting high levels of disorder are fundamentally flawed because they identify proteins that are well-known to become perfectly ordered — and to crystallize — when bound to their...