8FCA

Cryo-EM structure of the human TRPV4 - RhoA in complex with 4alpha-Phorbol 12,13-didecanoate

8FCA の概要

• エントリーDOI: 10.2210/pdb8fca/pdb
• EMDBエントリー: 28978
• 分子名称: Transient receptor potential cation channel subfamily V member 4, (1aR,1bS,4aS,7aS,7bS,8R,9R,9aS)-9a-(decanoyloxy)-4a,7b-dihydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-5-oxo-1a,1b,4,4a,5,7a,7b,8,9,9a-decahydro-1H-cyclopropa[3,4]benzo[1,2-e]azulen-9-yl decanoate, CHOLESTEROL HEMISUCCINATE (3 entities in total)
• 機能のキーワード: trpv4, rhoa, 4alpha-phorbol 12, 13-didecanoate, 4a-pdd, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 412869.82

構造登録者

Kwon, D.H.,Lee, S.-Y.,Zhang, F. (登録日: 2022-12-01, 公開日: 2023-07-12, 最終更新日: 2024-06-19)

主引用文献

Kwon, D.H.,Zhang, F.,McCray, B.A.,Feng, S.,Kumar, M.,Sullivan, J.M.,Im, W.,Sumner, C.J.,Lee, S.Y.
TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease.
Nat Commun, 14:3732-3732, 2023

PubMed Abstract: Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions. Gain-of-function mutations also cause hereditary neuromuscular disease. Here, we present cryo-EM structures of human TRPV4 in complex with RhoA in the ligand-free, antagonist-bound closed, and agonist-bound open states. These structures reveal the mechanism of ligand-dependent TRPV4 gating. Channel activation is associated with rigid-body rotation of the intracellular ankyrin repeat domain, but state-dependent interaction with membrane-anchored RhoA constrains this movement. Notably, many residues at the TRPV4-RhoA interface are mutated in disease and perturbing this interface by introducing mutations into either TRPV4 or RhoA increases TRPV4 channel activity. Together, these results suggest that RhoA serves as an auxiliary subunit for TRPV4, regulating TRPV4-mediated calcium homeostasis and disruption of TRPV4-RhoA interactions can lead to TRPV4-related neuromuscular disease. These insights will help facilitate TRPV4 therapeutics development.

PubMed: 37353484
DOI: 10.1038/s41467-023-39345-0

実験手法

ELECTRON MICROSCOPY (3.41 Å)