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

Structure
Avinash JaiganeshMarcos Sotomayor

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.

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Citations

Sep 24, 2020·Proceedings of the National Academy of Sciences of the United States of America·Deepanshu ChoudharyMarcos Sotomayor
May 11, 2019·Proceedings of the National Academy of Sciences of the United States of America·Tobias F BartschA J Hudspeth
Aug 9, 2020·Frontiers in Cell and Developmental Biology·Prathamesh T Nadar-PonniahRina Rosin-Arbesfeld
Dec 12, 2018·Biophysical Journal·Pedro De-la-TorreMarcos Sotomayor

Related Concepts

CDH23 protein, human
Cdh23 protein, mouse
Protein Domain
Metazoa
Calcium
Sensory Hearing Loss
Plasma Protein Binding Capacity
Liver Cell Adhesion Molecule
Protein Conformation, beta-Strand
Crystallography, X-Ray

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