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Structure of inner-ear protein is key to both hearing and inherited deafness
Date:4/16/2010

deafness are mutations specifically to the amino acids that bind the calcium. And these findings show how critical calcium ions, and the amino acid residues that bind them, are to the structure of this protein."

The research will appeared in the April 15 issue of Neuron.

To get an atomic-level view of how cadherin-23 behaves under normaland abnormalconditions, the scientists used a combination of protein crystallization and virtual-reality-like simulation that showed how the cadherin could break in billionths of a second.

Through crystallization, the researchers found that, like other members of the cadherin family, this protein contains three critical calcium ions between each of its 27 bead-like segments. The simulations showed that the ions formed a strong link between adjacent beads, sufficient to hold them together. In addition, a novel calcium-ion binding site was discovered at the very end of cadherin-23.

According to Corey, these binding sites "staple" the various subunits of cadherin-23 together and may also create the bond made with the second protein of the tip link.

To quantify exactly how strong these calcium-ion bonds were, the scientists loaded the protein's structure into a supercomputer, rendered its virtual likeness, then "stretched" the structure. They found that overall the protein acted more like a wire cable than a spring, as previously thought. This made it capable of withstanding forces ten-fold stronger than any that might be produced by normal sounds. When the scientists tested the structure against very great forces, however, it unraveled.

The researchers then elected to test how mutations similar to those associated with inherited deafness might alter cadherin-23's structure and affinity for calcium ions.

"We had the three-dimensional structure of the wild type protein," says Marcos Sotomayor, an HMS research fellow in neurobiology and co-lead author on the study,
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Contact: David Cameron
david_cameron@hms.harvard.edu
716-432-0441
Harvard Medical School
Source:Eurekalert

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