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.
Sensitivity, polarity, and conductance change in the response of vertebrate hair cells to controlled mechanical stimuli
Cross-links between stereocilia in the guinea pig organ of Corti, and their possible relation to sensory transduction
CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness
Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle
Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss
PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23
Spatiotemporal pattern and isoforms of cadherin 23 in wild type and waltzer mice during inner ear hair cell development
The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15
HKL-3000: the integration of data reduction and structure solution--from diffraction images to an initial model in minutes
PVS: a web server for protein sequence variability analysis tuned to facilitate conserved epitope discovery
MAGI-1, a candidate stereociliary scaffolding protein, associates with the tip-link component cadherin 23
Presence of interstereocilial links in waltzer mutants suggests Cdh23 is not essential for tip link formation
A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells
Assembling stable hair cell tip link complex via multidentate interactions between harmonin and cadherin 23
Harmonin-b, an actin-binding scaffold protein, is involved in the adaptation of mechanoelectrical transduction by sensory hair cells
The structure of the harmonin/sans complex reveals an unexpected interaction mode of the two Usher syndrome proteins
Structure of the N terminus of cadherin 23 reveals a new adhesion mechanism for a subset of cadherin superfamily members
Cadherin-23, myosin VIIa and harmonin, encoded by Usher syndrome type I genes, form a ternary complex and interact with membrane phospholipids
A new mouse mutant of the Cdh23 gene with early-onset hearing loss facilitates evaluation of otoprotection drugs
Development and regeneration of sensory transduction in auditory hair cells requires functional interaction between cadherin-23 and protocadherin-15
An ENU-induced mutation of Cdh23 causes congenital hearing loss, but no vestibular dysfunction, in mice
Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families
Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes
Geneious Basic: an integrated and extendable desktop software platform for the organization and analysis of sequence data
Large protein assemblies formed by multivalent interactions between cadherin23 and harmonin suggest a stable anchorage structure at the tip link of stereocilia
Prevalence and clinical features of hearing loss patients with CDH23 mutations: a large cohort study
Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice
Noddy, a mouse harboring a missense mutation in protocadherin-15, reveals the impact of disrupting a critical interaction site between tip-link cadherins in inner ear hair cells
Structure and Sequence Analyses of Clustered Protocadherins Reveal Antiparallel Interactions that Mediate Homophilic Specificity
ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules
Antiparallel protocadherin homodimers use distinct affinity- and specificity-mediating regions in cadherin repeats 1-4
Broken force dispersal network in tip-links by the mutations at the Ca2+ -binding residues induces hearing-loss
Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception
Elasticity of individual protocadherin 15 molecules implicates tip links as the gating springs for hearing
Single-molecule force spectroscopy reveals the dynamic strength of the hair-cell tip-link connection.
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