The All-Important Zipper

By Josie Glausiusz|Friday, September 01, 1995
For most of its 3.5-billion-year history, life on Earth consisted exclusively of single-celled organisms--bacteria, algae, amoebas, and the like. Then around 1 billion years ago the first multicellular organisms emerged. In fact, they emerged independently many times, presumably because cooperation among cells was such a good idea. Cooperation made possible a division of labor that promoted efficiency; it allowed the individual organism to grow larger and exploit resources no single cell could reach.

But before cells could cooperate, they had to solve a mechanical problem: how to stick together, and how to stick only to their own kind--so that a brain cell, say, would not in the course of embryonic development become attached to cells of the big toe. In vertebrates and in many invertebrates as well, the most important solution to this problem is a set of proteins that protrude from the surface of virtually all tissue cells. The proteins are known as calcium-dependent adhesion molecules, or cadherins for short. Their importance as a cell glue was discovered about a decade ago; take away the cadherins, researchers learned, and an embryo would simply fall apart. But only recently did a team of biochemists at Columbia figure out how cadherins do their job. It turns out that they don’t work like glue at all. They work like a zipper.

Earlier research had shown that cadherins penetrate a cell’s membrane and that they are anchored inside the cell to contractile proteins called actin filaments. In skin and other epithelial tissue, the actin filaments form a sturdy bundle that runs around the cell perimeter like an internal belt. Cadherins, it was assumed, join neighboring cells in a layer by somehow forming links between the cells’ actin belts. But when researchers isolated cadherins in solution, they found that the individual molecules barely adhered to one another at all. This was a real paradox, says Columbia graduate student Lawrence Shapiro. How could we be held together by molecules that really did not seem to stick together?

The solution to the paradox, Shapiro, Wayne Hendrickson, and their colleagues have discovered, is that it is not individual cadherin molecules that do the sticking. The Columbia researchers crystallized cadherins and determined their atomic structure by seeing how they diffracted X-rays. The X-ray crystallography showed that adjacent cadherins on the same cell would tend to form pairs. Furthermore, the tip of a cadherin from a neighboring cell would fit neatly between the two members of a pair, forming chemical bonds with both.

Some protein structures, when you see them, prompt an instant ‘Aha!’ says Shapiro. The cadherin structure was like that--the structural basis for how cadherins function was immediately apparent. They interdigitate like the teeth of a zipper. Although the adhesion between individual molecules is quite weak, the zipper brings together many thousands of cadherins from each cell surface. Shapiro thinks a ring of cadherin pairs may run right around a cell, anchored on the inside to the actin belt and zipping the cell tightly to all its neighbors.

The calcium in cadherins is essential to the mechanics of the zipper. Each cadherin, Shapiro and his colleagues found, consists of five domains, like beads on a string, and calcium ions are strategically placed at the boundaries between beads. The calcium stiffens the cadherins so that they stand up toward the other cell, says Shapiro.

Although all cadherins are structurally similar, the chemical bonds between their tips, Shapiro says, are different in different cell types--which is why brain cells bind only to brain cells and not to toe cells. The strong zipper holds tissue together, while the weakness of the individual bonds makes the cells resilient under stress. If individual bonds were strong, a pull on one cell might damage its neighbor. You’d tear the cadherins right out of its membrane, rupturing it, and the cell would die, says Shapiro. Whereas here we have weak interactions that can come apart a little bit at small areas without breaking the cell-cell bond or the cell surface. We think this is why nature has designed cell adhesion to work this way.
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