By Tanya Lewis
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.