8EKS

rat TRPV2 in nanodiscs in the presence of weak acid at pH 5

8EKS の概要

• エントリーDOI: 10.2210/pdb8eks/pdb
• EMDBエントリー: 28212
• 分子名称: Transient receptor potential cation channel subfamily V member 2, 1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE (2 entities in total)
• 機能のキーワード: ion channel, trp channel, membrane protein, tetramer, transport protein
• 由来する生物種: Rattus norvegicus (Norway rat)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 349286.09

構造登録者

Pumroy, R.A.,Moiseenkova-Bell, V.Y. (登録日: 2022-09-21, 公開日: 2023-09-27, 最終更新日: 2024-06-19)

主引用文献

Haug, F.M.,Pumroy, R.A.,Sridhar, A.,Pantke, S.,Dimek, F.,Fricke, T.C.,Hage, A.,Herzog, C.,Echtermeyer, F.G.,de la Roche, J.,Koh, A.,Kotecha, A.,Howard, R.J.,Lindahl, E.,Moiseenkova-Bell, V.,Leffler, A.
Functional and structural insights into activation of TRPV2 by weak acids.
Embo J., 43:2264-2290, 2024

PubMed Abstract: Transient receptor potential (TRP) ion channels are involved in the surveillance or regulation of the acid-base balance. Here, we demonstrate that weak carbonic acids, including acetic acid, lactic acid, and CO activate and sensitize TRPV2 through a mechanism requiring permeation through the cell membrane. TRPV2 channels in cell-free inside-out patches maintain weak acid-sensitivity, but protons applied on either side of the membrane do not induce channel activation or sensitization. The involvement of proton modulation sites for weak acid-sensitivity was supported by the identification of titratable extracellular (Glu495, Glu561) and intracellular (His521) residues on a cryo-EM structure of rat TRPV2 (rTRPV2) treated with acetic acid. Molecular dynamics simulations as well as patch clamp experiments on mutant rTRPV2 constructs confirmed that these residues are critical for weak acid-sensitivity. We also demonstrate that the pore residue Glu609 dictates an inhibition of weak acid-induced currents by extracellular calcium. Finally, TRPV2-expression in HEK293 cells is associated with an increased weak acid-induced cytotoxicity. Together, our data provide new insights into weak acids as endogenous modulators of TRPV2.

PubMed: 38671253
DOI: 10.1038/s44318-024-00106-4

実験手法

ELECTRON MICROSCOPY (3.1 Å)