TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease.
TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease.
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DOI：
10.1038/s41467-023-39345-0
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发表时间：
2023-06-23
影响因子：
16.6
通讯作者：
Lee, Seok-Yong
中科院分区：
文献类型：
--
作者：
Kwon, Do Hoon;Zhang, Feng;McCray, Brett A. A.;Feng, Shasha;Kumar, Meha;Sullivan, Jeremy M. M.;Im, Wonpil;Sumner, Charlotte J. J.;Lee, Seok-Yong
离子通道和小GTP酶之间的串扰在稳态和疾病中是至关重要的，但对这些相互作用的结构基础知之甚少。TRPV 4是一种多模态的钙渗透性阳离子通道，已成为多种疾病的潜在治疗靶点。功能获得性突变也会导致遗传性神经肌肉疾病。在这里，我们提出了冷冻EM结构的人TRPV 4在复杂的RhoA在无配体，拮抗剂结合的封闭，和激动剂结合的开放状态。这些结构揭示了配体依赖性TRPV 4门控的机制。通道激活与细胞内锚蛋白重复结构域的刚体旋转有关，但与膜锚定的RhoA的状态依赖性相互作用限制了这种运动。值得注意的是，TRPV 4-RhoA界面处的许多残基在疾病中突变，并且通过将突变引入TRPV 4或RhoA中来扰乱该界面增加TRPV 4通道活性。总之，这些结果表明，RhoA作为TRPV 4的辅助亚基，调节TRPV 4介导的钙稳态和TRPV 4-RhoA相互作用的破坏可导致TRPV 4相关的神经肌肉疾病。这些见解将有助于促进TRPV 4疗法的开发。尽管TRPV 4具有医学重要性，但配体介导的通道门控机制及其通过Rho GT3的调节尚不清楚。在这里，作者报告了TRPV 4与RhoA和配体复合的结构，为它们的功能提供了原子水平的见解。
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. Despite TRPV4’s medical importance, the mechanisms of ligand-mediated channel gating and its regulation by Rho GTPase are unclear. Here, the authors report the structures of TRPV4 in complex with RhoA and ligands, offering atomic-level insights into their functions.
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影响因子：
5.6
作者：
Chinigò G;Fiorio Pla A;Gkika D
通讯作者：
Gkika D
DOI：
10.1107/s2059798318009324
发表时间：
2018-09-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Klaholz BP;Moriarty NW;Poon BK;Sobolev OV;Terwilliger TC;Adams PD;Urzhumtsev A
通讯作者：
Urzhumtsev A
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3
作者：
Goyal, Navin;Skrdla, Pete;Cheriyan, Joseph
通讯作者：
Cheriyan, Joseph
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.