Zooming in on Cadherin-23: Structural Diversity and Potential Mechanisms of Inherited Deafness

Cadherin-23 (CDH23) is an essential component of hair-cell tip links, fine filaments that mediate inner-ear mechanotransduction. The extracellular domain of CDH23 forms about three-fourths of the tip link with 27 extracellular cadherin (EC) repeats that are structurally similar but not identical to each other. Calcium (Ca2+) coordination at the EC linker regions is key for tip-link elasticity and function. There are ∼116 sites in CDH23 affected by deafness-causing mutations, many of which alter conserved Ca2+-binding residues. Here we present crystal structures showing 18 CDH23 EC repeats, including the most and least conserved, a fragment carrying disease mutations, and EC repeats with non-canonical Ca2+-binding motif sequences and unusual secondary structure. Complementary experiments show deafness mutations' effects on stability and affinity for Ca2+. Additionally, a model of nine contiguous CDH23 EC repeats reveals helicity and potential parallel dimerization faces. Overall, our studies provide detailed structural insight into CDH23 function in mechanotransduction. [Display omitted] •Structures of 18 CDH23 extracellular cadherin (EC) “repeats” are presented•Non-canonical linker regions are at EC2-3, EC12-13, EC20-21, EC21-22, and EC24-25•The CDH23 EC17-25 fragment shows inherent helicity and a possible dimer interface•CDH23 missense mutations may affect structure and function by 5 distinct mechanisms Jaiganesh et al. present structures showing multiple parts of the extraordinarily large cadherin-23 protein, a key component of the inner-ear transduction apparatus mediating sound and balance perception. These structures reveal diverse features that determine cadherin-23 function in hearing and hereditary deafness.