PDBsum entry 4apx

Cell adhesion

PDB id: 4apx

Contents

Protein chains

208 a.a.

238 a.a.

Ligands

MES

GOL

Metals

_CL

_CA ×7

__K

Waters ×823

References listed in PDB file

Key reference

• Title: Structure of a force-Conveying cadherin bond essential for inner-Ear mechanotransduction.
• Authors: M.Sotomayor, W.A.Weihofen, R.Gaudet, D.P.Corey.
• Ref.: Nature, 2012, 492, 128-132.
• PubMed id: 23135401

Abstract

Hearing and balance use hair cells in the inner ear to transform mechanical stimuli into electrical signals. Mechanical force from sound waves or head movements is conveyed to hair-cell transduction channels by tip links, 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 and feature long extracellular domains that interact tip-to-tip 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, neural connectivity and cancer.