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基本情報
登録情報 | データベース: PDB / ID: 8fca | ||||||
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タイトル | Cryo-EM structure of the human TRPV4 - RhoA in complex with 4alpha-Phorbol 12,13-didecanoate | ||||||
![]() | Transient receptor potential cation channel subfamily V member 4 | ||||||
![]() | MEMBRANE PROTEIN / TRPV4 / RhoA / 4alpha-Phorbol 12 / 13-didecanoate / 4a-PDD | ||||||
機能・相同性 | ![]() blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / stretch-activated, monoatomic cation-selective, calcium channel activity / positive regulation of striated muscle contraction / calcium ion import into cytosol / positive regulation of macrophage inflammatory protein 1 alpha production / negative regulation of brown fat cell differentiation / positive regulation of microtubule depolymerization / hyperosmotic salinity response ...blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / stretch-activated, monoatomic cation-selective, calcium channel activity / positive regulation of striated muscle contraction / calcium ion import into cytosol / positive regulation of macrophage inflammatory protein 1 alpha production / negative regulation of brown fat cell differentiation / positive regulation of microtubule depolymerization / hyperosmotic salinity response / cortical microtubule organization / regulation of response to osmotic stress / positive regulation of chemokine (C-X-C motif) ligand 1 production / positive regulation of chemokine (C-C motif) ligand 5 production / cartilage development involved in endochondral bone morphogenesis / cellular hypotonic response / cellular hypotonic salinity response / multicellular organismal-level water homeostasis / positive regulation of vascular permeability / cellular response to osmotic stress / calcium ion import / osmosensory signaling pathway / cell volume homeostasis / positive regulation of monocyte chemotactic protein-1 production / cell-cell junction assembly / TRP channels / regulation of aerobic respiration / cortical actin cytoskeleton / positive regulation of macrophage chemotaxis / beta-tubulin binding / diet induced thermogenesis / microtubule polymerization / cytoplasmic microtubule / alpha-tubulin binding / calcium ion import across plasma membrane / monoatomic cation channel activity / response to mechanical stimulus / SH2 domain binding / filopodium / calcium ion transmembrane transport / protein kinase C binding / actin filament organization / adherens junction / positive regulation of JNK cascade / calcium channel activity / response to insulin / cilium / ruffle membrane / intracellular calcium ion homeostasis / positive regulation of inflammatory response / calcium ion transport / positive regulation of interleukin-6 production / actin filament binding / lamellipodium / negative regulation of neuron projection development / glucose homeostasis / actin binding / cellular response to heat / positive regulation of cytosolic calcium ion concentration / growth cone / actin cytoskeleton organization / microtubule binding / positive regulation of ERK1 and ERK2 cascade / calmodulin binding / response to hypoxia / apical plasma membrane / focal adhesion / lipid binding / protein kinase binding / cell surface / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / ATP binding / identical protein binding / membrane / metal ion binding / plasma membrane 類似検索 - 分子機能 | ||||||
生物種 | ![]() | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.41 Å | ||||||
![]() | Kwon, D.H. / Lee, S.-Y. / Zhang, F. | ||||||
資金援助 | ![]()
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![]() | ![]() タイトル: TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease. 著者: Do Hoon Kwon / Feng Zhang / Brett A McCray / Shasha Feng / Meha Kumar / Jeremy M Sullivan / Wonpil Im / Charlotte J Sumner / Seok-Yong Lee / ![]() 要旨: 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, ...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. | ||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 771.8 KB | 表示 | ![]() |
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-検証レポート
文書・要旨 | ![]() | 1.6 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.6 MB | 表示 | |
XML形式データ | ![]() | 71.8 KB | 表示 | |
CIF形式データ | ![]() | 104.8 KB | 表示 | |
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-関連構造データ
関連構造データ | ![]() 28978MC ![]() 8fc7C ![]() 8fc8C ![]() 8fc9C ![]() 8fcbC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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集合体
登録構造単位 | ![]()
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要素
#1: タンパク質 | 分子量: 102057.797 Da / 分子数: 4 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() #2: 化合物 | ChemComp-XS9 / ( #3: 化合物 | ChemComp-Y01 / 研究の焦点であるリガンドがあるか | Y | |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: CELL / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 | 名称: The complex of human TRPV4 with RhoA / タイプ: COMPLEX / Entity ID: #1 / 由来: RECOMBINANT |
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分子量 | 値: 0.45 MDa / 実験値: YES |
由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() |
緩衝液 | pH: 8 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 装置: LEICA EM GP / 凍結剤: ETHANE / 湿度: 95 % / 凍結前の試料温度: 281.15 K |
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電子顕微鏡撮影
顕微鏡 | モデル: FEI TITAN |
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電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 倍率(公称値): 81000 X / 最大 デフォーカス(公称値): 3000 nm / 最小 デフォーカス(公称値): 800 nm |
撮影 | 電子線照射量: 60 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.20.1_4487: / 分類: 精密化 | ||||||||||||||||||||||||
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3次元再構成 | 解像度: 3.41 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 244077 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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