4AQE

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

4AQE の概要

• エントリーDOI: 10.2210/pdb4aqe/pdb
• 関連するPDBエントリー: 2WBX 2WCP 2WD0 2WHV 4APX 4AQ8 4AQA
• 分子名称: CADHERIN-23, PROTOCADHERIN-15, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: cell adhesion, hearing, deafness, cdh23, pcdh15, heterophilic
• 由来する生物種: MUS MUSCULUS (HOUSE MOUSE); 詳細
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein (By similarity): Q99PF4 Q99PJ1
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 51883.97

構造登録者

Sotomayor, M.,Weihofen, W.,Gaudet, R.,Corey, D.P. (登録日: 2012-04-16, 公開日: 2012-11-07, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.27 Å)