FIGURE 10.4 The old and new models of the leucine zipper. The side chains do not interdigitate (left), but come together side by side (right).

Compelling as it was, the model of two cylindrical helices side by side, fastened together with a molecular zipper proved somewhat inaccurate. Instead, the leucine zipper is a structure well known to experts in protein folding, called a coiled coil, which Linus Pauling and Francis Crick had first proposed to be the structure of the protein keratin, independently of each other, nearly 40 years earlier. Rather than lying side by side, the two helices of a coiled coil wind around each other in a super helix, like a pair of slinkies wrapped around each other or like the twining of rope.

Instead of one zipper running the length of the two helices, the structure of the binding mechanism is more like a series of very short zippers forming individual connections between the two helices (see Figure 10.4).

THE LEUCINE ZIPPER IS A COILED COIL

It was a freshly minted graduate of Smith college, who was working as a technician in Peter Kim's lab at the Massachusetts Institute of Technology, who spotted McKnight's mistakes. Her insight ultimately led to her Ph.D.

"McKnight's paper came out in June, 1988," says Alber. "The week it came out, [Erin] O'Shea read it. Peter and I had come back from a meeting, and Erin ran up to us in the hall, gave him the papers, and said, 'Read these by tomorrow, the peptide is on the synthesizer'." O'Shea, a sure-footed young woman of 26, is more modest about her achievement, explaining that she was quite familiar with coiled coils. "I had majored in biochemistry, and my advisor worked on coiled coils." So it was not surprising that she could spot a distorted one.

"It was evident from what I read that McKnight's [model] couldn't be correct," says O'Shea. "It takes 3.6 amino acids to make one full turn of a protein helix," she explains. "If the helical repeat were 3.5, the leucines, spaced every seventh amino acid, would fall on top of each other in the coil," as McKnight had described it. "One-tenth of a helix doesn't sound like much, but it is enough to make the ridge of leucines spiral around the helix, instead of lying flat.''



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