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"...a better understanding of how these molecules bind to one another may eventually allow the use of gene therapy to devise potential cures."
Deborah Leckband

Mechanism Found that Appears to Keep Body Tissues Together
by James E. Kloeppel

Scientists studying the adhesive properties of cadherin–a protein that binds cells into soft tissue–have found a built-in safety mechanism that may keep cells from ripping apart.

"Cadherins hold soft tissues together by binding to identical proteins on adjacent cell surfaces," said Deborah Leckband, professor of chemical engineering at the University of Illinois. "The resulting strong, intercellular junctions play an important role in holding our tissues together. The proteins are also important in facilitating the cell-sorting process during embryonic development."

Because there are a number of diseases "associated with malfunctions or mutations of the cadherin protein," Leckband said, "a better understanding of how these molecules bind to one another may eventually allow the use of gene therapy to devise potential cures."

To study the adhesive properties of cadherin, Leckband and her colleagues used a surface-force apparatus to measure the molecular forces between two cadherin monolayers as a function of the distance between them. Leckband’s colleagues were graduate student Sanjeeve Sivasankar and postdoctoral research associate Nickolay Lavrik at the University of Illinois at Urbana-Champaign and graduate student Bill Brieher and cell biologist Barry Gumbiner at the Memorial Sloan-Kettering Cancer Center in New York City.

"Our direct-force measurements show that the current model for cadherin is insufficient to explain how this protein binds to its neighbors," Leckband said. "We found that the proteins adhere strongest when they overlap completely; not when just their ends touch, as the model had suggested. In fact, our measurements indicate that the ends of the proteins contribute very little to the binding process."

One of the scientists’ most surprising findings, however, was the unusual way in which the proteins detached from one another. "Instead of simply snapping apart, the cadherins first moved apart slowly, then built up speed, and finally jumped out of contact," Leckband said. "This was the first time we had witnessed an unbinding profile occurring in three distinct stages. Clearly, something is preventing the proteins from abruptly ripping apart."

The sluggish separation behavior could be a result of multiple adhesive contacts between different parts of the proteins, Leckband said. The scientists have identified at least two configurations in which the proteins bind, and these multiple interactions could retard or prevent the abrupt failure of the adhesive junctions.

"The successive rupture of these multiple contacts during protein detachment appears to form a kind of build-in ‘ratcheting’ mechanism, which further impedes overall junction failure," Leckband said. "While we still have lots to learn, these measurements are changing the way we look at cadherins and how they bind."

The researchers reported their findings in the Oct. 12, 1999, issue of the Proceedings of the National Academy of Science.