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Structural determinants of cadherin-23 function in hearing and deafness.

Sotomayor M, Weihofen WA, Gaudet R, Corey DP
Neuron 66 85-100 (2010)
Related entries: 2wbx, 2wcp, 2wd0

Cited: 84 times
EuropePMC logo PMID: 20399731

Abstract

The hair-cell tip link, a fine filament directly conveying force to mechanosensitive transduction channels, is composed of two proteins, protocadherin-15 and cadherin-23, whose mutation causes deafness. However, their molecular structure, elasticity, and deafness-related structural defects are unknown. We present crystal structures of the first and second extracellular cadherin repeats of cadherin-23. Overall, structures show typical cadherin folds, but reveal an elongated N terminus that precludes classical cadherin interactions and contributes to an N-terminal Ca(2+)-binding site. The deafness mutation D101G, in the linker region between the repeats, causes a slight bend between repeats and decreases Ca(2+) affinity. Molecular dynamics simulations suggest that cadherin-23 repeats are stiff and that either removing Ca(2+) or mutating Ca(2+)-binding residues reduces rigidity and unfolding strength. The structures define an uncharacterized cadherin family and, with simulations, suggest mechanisms underlying inherited deafness and how cadherin-23 may bind with itself and with protocadherin-15 to form the tip link.

Reviews - 2whv mentioned but not cited (1)

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Articles - 2whv mentioned but not cited (6)

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Reviews citing this publication (23)

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Articles citing this publication (54)

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