Structural Determinants of Cadherin-23 Function in Hearing and Deafness

Journal Article · Mon Jun 21 04:00:00 EDT 2010 · Neuron

DOI:https://doi.org/10.1016/j.neuron.2010.03.028· OSTI ID:1002374

Sotomayor, Marcos; Weihofen, Wilhelm A; Gaudet, Rachelle; Corey, David P ^[1]

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1. Harvard-Med

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{sup 2+}-binding site. The deafness mutation D101G, in the linker region between the repeats, causes a slight bend between repeats and decreases Ca{sup 2+} affinity. Molecular dynamics simulations suggest that cadherin-23 repeats are stiff and that either removing Ca{sup 2+} or mutating Ca{sup 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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1002374
• Journal Information: Neuron, Journal Name: Neuron Journal Issue: (1) ; 04, 2010 Vol. 66; ISSN 0896-6273; ISSN NERNET
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
AFFINITY
CRYSTAL STRUCTURE
DEFECTS
ELASTICITY
MOLECULAR STRUCTURE
MUTATIONS
PROTEINS
RESIDUES