7T6M

Cryo-EM structure of TRPV5 in nanodiscs with PI(4,5)P2 at pH6 state 1

7T6M の概要

• エントリーDOI: 10.2210/pdb7t6m/pdb
• EMDBエントリー: 25716 25717 25718 25719 25720 25721 25722 25723 25724 25725
• 分子名称: Transient receptor potential cation channel subfamily V member 5, [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate (2 entities in total)
• 機能のキーワード: calcium, ion channel, kidney, transport protein
• 由来する生物種: Oryctolagus cuniculus (rabbit)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 338124.61

構造登録者

Fluck, E.C.,Yazici, A.T.,Rohacs, T.,Moiseenkova-Bell, V.Y. (登録日: 2021-12-14, 公開日: 2022-05-04, 最終更新日: 2024-02-28)

主引用文献

Fluck, E.C.,Yazici, A.T.,Rohacs, T.,Moiseenkova-Bell, V.Y.
Structural basis of TRPV5 regulation by physiological and pathophysiological modulators.
Cell Rep, 39:110737-110737, 2022

PubMed Abstract: Transient receptor potential vanilloid 5 (TRPV5) is a kidney-specific Ca-selective ion channel that plays a key role in Ca homeostasis. The basal activity of TRPV5 is balanced through activation by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P) and inhibition by Ca-bound calmodulin (CaM). Parathyroid hormone (PTH), the key extrinsic regulator of Ca homeostasis, increases the activity of TRPV5 via protein kinase A (PKA)-mediated phosphorylation. Metabolic acidosis leads to reduced TRPV5 activity independent of PTH, causing hypercalciuria. Using cryoelectron microscopy (cryo-EM), we show that low pH inhibits TRPV5 by precluding PI(4,5)P activation. We capture intermediate conformations at low pH, revealing a transition from open to closed state. In addition, we demonstrate that PI(4,5)P is the primary modulator of channel gating, yet PKA controls TRPV5 activity by preventing CaM binding and channel inactivation. Our data provide detailed molecular mechanisms for regulation of TRPV5 by two key extrinsic modulators, low pH and PKA.

PubMed: 35476976
DOI: 10.1016/j.celrep.2022.110737

実験手法

ELECTRON MICROSCOPY (2.8 Å)