4AQE

CRYSTAL STRUCTURE OF DEAFNESS ASSOCIATED MUTANT MOUSE CADHERIN-23 EC1- 2S70P AND PROTOCADHERIN-15 EC1-2 FORM I

Summary for 4AQE

• Entry DOI: 10.2210/pdb4aqe/pdb
• Related: 2WBX 2WCP 2WD0 2WHV 4APX 4AQ8 4AQA
• Descriptor: CADHERIN-23, PROTOCADHERIN-15, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: cell adhesion, hearing, deafness, cdh23, pcdh15, heterophilic
• Biological source: MUS MUSCULUS (HOUSE MOUSE); More
• Cellular location: Cell membrane; Single-pass type I membrane protein (By similarity): Q99PF4 Q99PJ1
• Total number of polymer chains: 2
• Total formula weight: 51883.97

Authors

Sotomayor, M.,Weihofen, W.,Gaudet, R.,Corey, D.P. (deposition date: 2012-04-16, release date: 2012-11-07, Last modification date: 2024-10-16)

Primary citation

Sotomayor, M.,Weihofen, W.,Gaudet, R.,Corey, D.P.
Structure of a Force-Conveying Cadherin Bond Essential for Inner-Ear Mechanotransduction
Nature, 492:128-, 2012

PubMed 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.

PubMed: 23135401
DOI: 10.1038/NATURE11590

Experimental method

X-RAY DIFFRACTION (2.27 Å)