Structure of a non-mammalian cadherin heterodimer suggests a general binding mechanism essential for hair-cell mechanotransduction.

Abstract

Vertebrate hair cells have evolved over 500 million years to function as exquisitely precise and robust mechanosensors that transform mechanical stimuli into electrochemical signals for brain processing. Critical for this process of mechanotransduction is the tip link, a fine protein filament conveying force to gate ion channels and trigger sensory perception. In various mammals, cadherin-23 and protocadherin-15 interact to form tip links. Crystal structures of mouse protein fragments have shown that this interaction is mediated by the protein tips (EC1-2), which engage in an antiparallel “handshake complex” essential for hair-cell mechanotransduction that has been validated in vitro and in vivo. However, less is known about non-mammalian tip links. There is evidence supporting the existence of tip links made of cadherin-23 and protocadherin-15 in birds and fish, and our surface plasmon resonance experiments suggest that reptile tip-link proteins also form handshake complexes. Here we report the X-ray crystal structure of the non-mammalian catfish (Pangasianodon hypophthalmus) cadherin-23 and protocadherin-15b EC1-2 heterodimer complex at 2.6-Å resolution. The catfish protein fragments arrange in an antiparallel dimer that strongly resembles that of the mammalian handshake complex, suggesting a general binding mechanism for cadherin-23 and protocadherin-15 throughout vertebrates and paralogues.