- EMDB-40959: Cryo-EM structure of human TRPV4 ankyrin repeat domain in complex... -
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データベース: EMDB / ID: EMD-40959
タイトル
Cryo-EM structure of human TRPV4 ankyrin repeat domain in complex with GTPase RhoA
マップデータ
試料
複合体: human TRPV4 ankyrin repeat domain in complex with GTPase RhoA
タンパク質・ペプチド: Transient receptor potential cation channel subfamily V member 4-Enhanced green fluorescent protein chimera
タンパク質・ペプチド: Transforming protein RhoA
リガンド: GUANOSINE-5'-DIPHOSPHATE
キーワード
transient receptor potential V family member 4 / TRP / channel / TRPV4 / TRP channels / membrane protein / GTPase / transforming protein RhoA / RhoA / ankyrin repeat domain / GDP / guanosine diphosphate
機能・相同性
機能・相同性情報
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 / aortic valve formation / alpha-beta T cell lineage commitment / mitotic cleavage furrow formation / bone trabecula morphogenesis / positive regulation of lipase activity / endothelial tube lumen extension / skeletal muscle satellite cell migration / positive regulation of vascular associated smooth muscle contraction / angiotensin-mediated vasoconstriction involved in regulation of systemic arterial blood pressure / SLIT2:ROBO1 increases RHOA activity / RHO GTPases Activate Rhotekin and Rhophilins / Roundabout signaling pathway / cellular hypotonic response / negative regulation of intracellular steroid hormone receptor signaling pathway / Axonal growth inhibition (RHOA activation) / Axonal growth stimulation / cellular hypotonic salinity response / regulation of neural precursor cell proliferation / cleavage furrow formation / regulation of modification of postsynaptic actin cytoskeleton / regulation of osteoblast proliferation / multicellular organismal-level water homeostasis / forebrain radial glial cell differentiation / cell junction assembly / apical junction assembly / regulation of systemic arterial blood pressure by endothelin / positive regulation of vascular permeability / negative regulation of cell migration involved in sprouting angiogenesis / cellular response to chemokine / negative regulation of cell size / beta selection / establishment of epithelial cell apical/basal polarity / regulation of modification of postsynaptic structure / RHO GTPases Activate ROCKs / negative regulation of oxidative phosphorylation / negative regulation of motor neuron apoptotic process / cellular response to osmotic stress / calcium ion import / osmosensory signaling pathway / cell volume homeostasis / RHO GTPases activate CIT / positive regulation of monocyte chemotactic protein-1 production / Sema4D induced cell migration and growth-cone collapse / PCP/CE pathway / RHO GTPases activate KTN1 / apolipoprotein A-I-mediated signaling pathway / positive regulation of podosome assembly / cell-cell junction assembly / negative regulation of cell-substrate adhesion / TRP channels / positive regulation of alpha-beta T cell differentiation / ossification involved in bone maturation / odontogenesis / Wnt signaling pathway, planar cell polarity pathway / Sema4D mediated inhibition of cell attachment and migration / motor neuron apoptotic process / positive regulation of leukocyte adhesion to vascular endothelial cell / PI3K/AKT activation / wound healing, spreading of cells / apical junction complex / regulation of neuron projection development / regulation of focal adhesion assembly / negative chemotaxis / regulation of aerobic respiration / cortical actin cytoskeleton / myosin binding / EPHA-mediated growth cone collapse / positive regulation of macrophage chemotaxis / stress fiber assembly / beta-tubulin binding / RHOC GTPase cycle / diet induced thermogenesis / positive regulation of cytokinesis / cerebral cortex cell migration / androgen receptor signaling pathway / microtubule polymerization / cytoplasmic microtubule / cellular response to cytokine stimulus / ERBB2 Regulates Cell Motility / cleavage furrow / semaphorin-plexin signaling pathway / Rho protein signal transduction / ficolin-1-rich granule membrane / mitotic spindle assembly / alpha-tubulin binding 類似検索 - 分子機能
Transient receptor potential cation channel subfamily V member 4 / Small GTPase Rho / small GTPase Rho family profile. / Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / Ankyrin repeat ...Transient receptor potential cation channel subfamily V member 4 / Small GTPase Rho / small GTPase Rho family profile. / Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / Ankyrin repeat / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein / Small GTP-binding protein domain / P-loop containing nucleoside triphosphate hydrolase 類似検索 - ドメイン・相同性
Enhanced green fluorescent protein / Transforming protein RhoA / Transient receptor potential cation channel subfamily V member 4 類似検索 - 構成要素
生物種
Homo sapiens (ヒト) / Human cytomegalovirus (ヘルペスウイルス)
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)
R01 AR078814
米国
National Institutes of Health/National Cancer Institute (NIH/NCI)
R01 CA206573
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01 NS083660
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01 NS107253
米国
German Research Foundation (DFG)
464295817
ドイツ
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R01 HL096647
米国
引用
ジャーナル: Nat Commun / 年: 2023 タイトル: Structure of human TRPV4 in complex with GTPase RhoA. 著者: Kirill D Nadezhdin / Irina A Talyzina / Aravind Parthasarathy / Arthur Neuberger / David X Zhang / Alexander I Sobolevsky / 要旨: Transient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It is involved in ...Transient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It is involved in thermogenesis, regulation of vascular tone, bone homeostasis, renal and pulmonary functions. TRPV4 is implicated in neuromuscular and skeletal disorders, pulmonary edema, and cancers, and represents an important drug target. The cytoskeletal remodeling GTPase RhoA has been shown to suppress TRPV4 activity. Here, we present a structure of the human TRPV4-RhoA complex that shows RhoA interaction with the membrane-facing surface of the TRPV4 ankyrin repeat domains. The contact interface reveals residues that are mutated in neuropathies, providing an insight into the disease pathogenesis. We also identify the binding sites of the TRPV4 agonist 4α-PDD and the inhibitor HC-067047 at the base of the S1-S4 bundle, and show that agonist binding leads to pore opening, while channel inhibition involves a π-to-α transition in the pore-forming helix S6. Our structures elucidate the interaction interface between hTRPV4 and RhoA, as well as residues at this interface that are involved in TRPV4 disease-causing mutations. They shed light on TRPV4 activation and inhibition and provide a template for the design of future therapeutics for treatment of TRPV4-related diseases.