Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction
Top Cited Papers
Open Access
- 7 November 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 492 (7427), 128-132
- https://doi.org/10.1038/nature11590
Abstract
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. 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 signals1. Mechanical force from sound waves or head movements is conveyed to hair-cell transduction channels by tip links2,3, fine filaments formed by two atypical cadherins known as protocadherin 15 and cadherin 23 (refs 4, 5). These two proteins are involved in inherited deafness6,7,8,9,10 and feature long extracellular domains that interact tip-to-tip5,11 in a Ca2+-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 Ca2+ removal owing to increased flexure of Ca2+-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 morphogenesis12,13, neural connectivity14 and cancer15.Keywords
This publication has 47 references indexed in Scilit:
- Thinking outside the cell: how cadherins drive adhesionTrends in Cell Biology, 2012
- Control of Neuronal Morphology by the Atypical Cadherin Fat3Neuron, 2011
- Structural Determinants of Cadherin-23 Function in Hearing and DeafnessNeuron, 2010
- Mechanotransduction by Hair Cells: Models, Molecules, and MechanismsCell, 2009
- Gene structure and mutant alleles of PCDH15: nonsyndromic deafness DFNB23 and type 1 Usher syndromeHuman Genetics, 2008
- Inference of Macromolecular Assemblies from Crystalline StateJournal of Molecular Biology, 2007
- Scalable molecular dynamics with NAMDJournal of Computational Chemistry, 2005
- Extending the treatment of backbone energetics in protein force fields: Limitations of gas‐phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulationsJournal of Computational Chemistry, 2004
- [20] Processing of X-ray diffraction data collected in oscillation modeMethods in Enzymology, 1997
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996