Structural determinants of cadherin-23 function in hearing and deafness.
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.
Sotomayor
Marcos
M
Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Weihofen
Wilhelm A
WA
Gaudet
Rachelle
R
Corey
David P
DP
D000818:Animals; D001665:Binding Sites; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism; D003638:Deafness / Q000378:metabolism / Q000503:physiopathology*; D006198:Hair Cells, Auditory / Q000378:metabolism*; D006309:Hearing / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000502:physiology; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D011498:Protein Precursors / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
C418976:CDHR15 protein, mouse; D000070585:Cadherin Related Proteins; D015820:Cadherins; C499091:Cdh23 protein, mouse; D011498:Protein Precursors
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