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Strings attached: Sound perception and brain wiring enabled by cadherins
Author(s) -
Sotomayor Marcos
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.102.2
Subject(s) - protocadherin , cadherin , mechanosensation , biology , microbiology and biotechnology , superfamily , neuroscience , genetics , receptor , ion channel , cell
Cadherins form a large superfamily of proteins essential for morphogenesis, neuronal connectivity, and tissue integrity. Two atypical members of this superfamily, cadherin‐23 (cdh23) and protocadherin‐15 (pcdh15), are also involved in hereditary deafness and blindness. In the inner ear, these two proteins interact to form the tip link, a fine filament that pulls open transduction channels to initiate a cascade of events leading to sensory perception. Here we present structural, computational, and biophysical experiments that reveal unique properties of the tip link's extracellular cadherin (EC) repeats. Our crystal structures, simulations, and binding assays show how the N‐terminus of pcdh15 and several of its variants form a calcium‐dependent heterophilic complex with the N‐terminus of cdh23. In addition, structures and simulations of other domains of cdh23 and pcdh15 reveal unusual inter‐repeat linker regions that may alter the tertiary structure and elasticity of these proteins. Overall, our results provide a molecular view of tip link mechanics and identify the structural determinants of cdh23 and pcdh15 function in vertebrate mechanosensation. Support or Funding Information NIH NIDCD and Alfred P. Sloan Foundation.