Structural determinants of cadherin-23 function in hearing and deafness.
Publication Type:Journal Article
Source:Neuron, Volume 66, Issue 1, p.85-100 (2010)
Keywords:Animals, Binding Sites, Cadherins, Deafness, Hair Cells, Auditory, Hearing, Mechanotransduction, Cellular, Mice, Models, Molecular, Protein Conformation, Protein Precursors, Structure-Activity Relationship
<p>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.</p>