Journal Article

Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction

Corey, David P., Weihofen, Wilhelm A., Gaudet, Rachelle, Sotomayor, Marcos

2012

Overview

A combination of structural, computational and biophysical tools is used to characterize the bond between tip-link proteins protocadherin 15 and cadherin 23, which have an essential role in inner-ear mechanotransduction; the bond, involving an extended protein handshake, is found to be affected by deafness mutations and is mechanically strong enough to resist forces in hair cells, adding to our understanding of hair-cell sensory transduction and interactions among cadherins. Mechanism of hair-cell sensory transduction Hair cells in the inner ear transform mechanical stimuli into electrical signals that are crucial for hearing and balance. These cells contain actin-rich stereocilia that are interconnected by filaments such as the tip link, which forms the mechanotransduction apparatus. The adhesion molecules protocadherin 15 and cadherin 23 form the tip link. In this study, David Corey et al . use a combination of structural and biophysical experiments to characterize the bond between cadherin 23 and protocadherin 15. The bond is mechanically strong enough to resist forces in hair cells and requires calcium to maintain stability. These results provide molecular insights into the mechanics of hair-cell sensory transduction. Hearing and balance use hair cells in the inner ear to transform mechanical stimuli into electrical signals 1 . Mechanical force from sound waves or head movements is conveyed to hair-cell transduction channels by tip links 2 , 3 , fine filaments formed by two atypical cadherins known as protocadherin 15 and cadherin 23 (refs 4 , 5 ). These two proteins are involved in inherited deafness 6 , 7 , 8 , 9 , 10 and feature long extracellular domains that interact tip-to-tip 5 , 11 in a Ca 2+ -dependent manner. However, the molecular architecture of this complex is unknown. Here we combine crystallography, molecular dynamics simulations and binding experiments to characterize the protocadherin 15–cadherin 23 bond. We find a unique cadherin interaction mechanism, in which the two most amino-terminal cadherin repeats (extracellular cadherin repeats 1 and 2) of each protein interact to form an overlapped, antiparallel heterodimer. Simulations predict that this tip-link bond is mechanically strong enough to resist forces in hair cells. In addition, the complex is shown to become unstable in response to Ca 2+ removal owing to increased flexure of Ca 2+ -free cadherin repeats. Finally, we use structures and biochemical measurements to study the molecular mechanisms by which deafness mutations disrupt tip-link function. Overall, our results shed light on the molecular mechanics of hair-cell sensory transduction and on new interaction mechanisms for cadherins, a large protein family implicated in tissue and organ morphogenesis 12 , 13 , neural connectivity 14 and cancer 15 .

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/2619/1592 / 631/535 / 631/80/79/1902 / 631/80/79/2066 / Analytical, structural and metabolic biochemistry / Animals / Binding sites / Biological and medical sciences / Cadherins / Cadherins - chemistry / Cadherins - genetics / Cadherins - metabolism / Calcium - metabolism / Calcium - pharmacology / Chemical bonds / Chromatography, Gel / Crystal lattices / Crystallography / Crystallography, X-Ray / Deafness - genetics / Ear, Inner - cytology / Ear, Inner - physiology / Experiments / Fundamental and applied biological sciences. Psychology / Hair / Hair cells (Mechanoreceptors) / Hearing / Humanities and Social Sciences / Labyrinth (Ear) / letter / Mechanical properties / Mechanotransduction, Cellular - physiology / Mice / Models, Molecular / Molecular and cellular biology / Molecular dynamics / Molecular Dynamics Simulation / multidisciplinary / Mutagenesis, Site-Directed / Mutation / Mutation - genetics / Physiological aspects / Physiological research / Properties / Protein Binding - drug effects / Protein Multimerization - drug effects / Protein Precursors - chemistry / Protein Precursors - genetics / Protein Precursors - metabolism / Proteins / Repetitive Sequences, Amino Acid / Science / Sound waves / Testing