TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease
Abstract 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 co...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39345-0 |
| _version_ | 1827916836799250432 |
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| author | Do Hoon Kwon Feng Zhang Brett A. McCray Shasha Feng Meha Kumar Jeremy M. Sullivan Wonpil Im Charlotte J. Sumner Seok-Yong Lee |
| author_facet | Do Hoon Kwon Feng Zhang Brett A. McCray Shasha Feng Meha Kumar Jeremy M. Sullivan Wonpil Im Charlotte J. Sumner Seok-Yong Lee |
| author_sort | Do Hoon Kwon |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-13T03:19:56Z |
| format | Article |
| id | doaj.art-331aacbb49b14346b60ba84795aa8594 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T03:19:56Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-331aacbb49b14346b60ba84795aa85942023-06-25T11:22:11ZengNature PortfolioNature Communications2041-17232023-06-0114111510.1038/s41467-023-39345-0TRPV4-Rho GTPase complex structures reveal mechanisms of gating and diseaseDo Hoon Kwon0Feng Zhang1Brett A. McCray2Shasha Feng3Meha Kumar4Jeremy M. Sullivan5Wonpil Im6Charlotte J. Sumner7Seok-Yong Lee8Department of Biochemistry, Duke University School of MedicineDepartment of Biochemistry, Duke University School of MedicineDepartment of Neurology, Johns Hopkins University School of MedicineDepartments of Biological Sciences, Chemistry, and Bioengineering, Lehigh UniversityDepartment of Neurology, Johns Hopkins University School of MedicineDepartment of Neurology, Johns Hopkins University School of MedicineDepartments of Biological Sciences, Chemistry, and Bioengineering, Lehigh UniversityDepartment of Neurology, Johns Hopkins University School of MedicineDepartment of Biochemistry, Duke University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-023-39345-0 |
| spellingShingle | Do Hoon Kwon Feng Zhang Brett A. McCray Shasha Feng Meha Kumar Jeremy M. Sullivan Wonpil Im Charlotte J. Sumner Seok-Yong Lee TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease Nature Communications |
| title | TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease |
| title_full | TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease |
| title_fullStr | TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease |
| title_full_unstemmed | TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease |
| title_short | TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease |
| title_sort | trpv4 rho gtpase complex structures reveal mechanisms of gating and disease |
| url | https://doi.org/10.1038/s41467-023-39345-0 |
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