3W9F

Crystal structure of the ankyrin repeat domain of chicken TRPV4 in complex with IP3

3W9F の概要

• エントリーDOI: 10.2210/pdb3w9f/pdb
• 関連するPDBエントリー: 3W9G
• 分子名称: Vanilloid receptor-related osmotically activated channel protein, D-MYO-INOSITOL-1,4,5-TRIPHOSPHATE (3 entities in total)
• 機能のキーワード: ankyrin repeat domain, ard, transport protein
• 由来する生物種: Gallus gallus (bantam,chickens)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 119595.95

構造登録者

Itoh, Y.,Hamada-nakahara, S.,Suetsugu, S. (登録日: 2013-04-04, 公開日: 2014-04-09, 最終更新日: 2023-11-08)

主引用文献

Takahashi, N.,Hamada-Nakahara, S.,Itoh, Y.,Takemura, K.,Shimada, A.,Ueda, Y.,Kitamata, M.,Matsuoka, R.,Hanawa-Suetsugu, K.,Senju, Y.,Mori, M.X.,Kiyonaka, S.,Kohda, D.,Kitao, A.,Mori, Y.,Suetsugu, S.
TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2
Nat Commun, 5:4994-4994, 2014

PubMed Abstract: Mutations in the ankyrin repeat domain (ARD) of TRPV4 are responsible for several channelopathies, including Charcot-Marie-Tooth disease type 2C and congenital distal and scapuloperoneal spinal muscular atrophy. However, the molecular pathogenesis mediated by these mutations remains elusive, mainly due to limited understanding of the TRPV4 ARD function. Here we show that phosphoinositide binding to the TRPV4 ARD leads to suppression of the channel activity. Among the phosphoinositides, phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) most potently binds to the TRPV4 ARD. The crystal structure of the TRPV4 ARD in complex with inositol-1,4,5-trisphosphate, the head-group of PI(4,5)P2, and the molecular-dynamics simulations revealed the PI(4,5)P2-binding amino-acid residues. The TRPV4 channel activities were increased by titration or hydrolysis of membrane PI(4,5)P2. Notably, disease-associated TRPV4 mutations that cause a gain-of-function phenotype abolished PI(4,5)P2 binding and PI(4,5)P2 sensitivity. These findings identify TRPV4 ARD as a lipid-binding domain in which interactions with PI(4,5)P2 normalize the channel activity in TRPV4.

PubMed: 25256292
DOI: 10.1038/ncomms5994

実験手法

X-RAY DIFFRACTION (1.9 Å)