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


ABSTRACT: 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.

SUBMITTER: Jaiganesh A 

PROVIDER: S-EPMC6375707 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Jaiganesh Avinash A   De-la-Torre Pedro P   Patel Aniket A AA   Termine Domenic J DJ   Velez-Cortes Florencia F   Chen Conghui C   Sotomayor Marcos M  

Structure (London, England : 1993) 20180719 9


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 (Ca<sup>2+</sup>) 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 w  ...[more]

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