Disorder at Work

                                                          Disorder at Work
Richard Kriwacki refused to give up on his protein. He had tried again and again to determine its three-dimensional shape, but in every experiment, the protein looked no more structured than a piece of cooked spaghetti.
Normally, this lack of form would be a sign that the protein had been destroyed, yet Kriwacki knew for a fact it could still do its job in controlling cell division. While discussing the conundrum with his adviser in the atrium of their La Jolla, Calif., lab, insight dawned: Maybe the floppy protein didn’t take shape until it attached to another protein. Kriwacki raced off to do yet another experiment, this time combining his protein, p21, with a partner. Sure enough, Kriwacki got what he was looking for. Once joined, a seemingly ruined mess gave way to a neatly folded structure. The finding defied a foundational dogma of biology, that structure determines function.
Nearly everything the human body does, from shuttling oxygen through the bloodstream to digesting a meal, relies on proteins. These biological workhorses are composed of chains of molecules called amino acids. Whenever a chain is made, conventional scientific wisdom says, electrical forces cause it to immediately bend into helical ribbons and tight zigzags, which twist further into even more defined three-dimensional forms. The resulting shape determines what other molecular players the protein can bind to and thus what it can accomplish in a cell. Unfolded proteins were thought to result only from intolerable conditions that render a protein useless, such as extreme heat or acidity.
But since around the time of Kriwacki’s discovery more than 15 years ago, disorder has surfaced as a key player in the protein world. “Intrinsically disordered proteins,” or IDPs, turn out to play vital parts in controlling cellular processes. More than one-third of all human proteins, in fact, may be partially or completely disordered in structure, floating around like strands of wet noodles. “The roles that disordered regions can play are quite diverse,” says Kriwacki, now at St. Jude Children’s Research Hospital in Memphis, Tenn.
 To better understand how something so flexible can be functional, researchers are now taking a closer look at how the disordered proteins interact with other proteins. The disordered dissidents can behave as switches, quickly turning cellular processes on or off in response to changing conditions, or as shape-shifting ensembles that integrate multiple signals before telling a cell to get a job done. Studying the interactions of intrinsically disordered proteins may even yield insight into certain diseases and lead to new treatments.
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