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TitleTRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 3732, Year 2023
Publish dateJun 23, 2023
AuthorsDo Hoon Kwon / Feng Zhang / Brett A McCray / Shasha Feng / Meha Kumar / Jeremy M Sullivan / Wonpil Im / Charlotte J Sumner / Seok-Yong Lee /
PubMed AbstractCrosstalk 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.
External linksNat Commun / PubMed:37353484 / PubMed Central
MethodsEM (single particle)
Resolution3.2 - 3.75 Å
Structure data

EMDB-28975, PDB-8fc7:
Cryo-EM structure of the human TRPV4 - RhoA in complex with GSK2798745
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-28976, PDB-8fc8:
Cryo-EM structure of the human TRPV4 in complex with GSK1016790A
PDB-8fcb: Cryo-EM structure of the human TRPV4 - RhoA in complex with GSK1016790A
Method: EM (single particle) / Resolution: 3.47 Å

EMDB-28977, PDB-8fc9:
Cryo-EM structure of the human TRPV4 - RhoA, apo condition
Method: EM (single particle) / Resolution: 3.75 Å

EMDB-28978, PDB-8fca:
Cryo-EM structure of the human TRPV4 - RhoA in complex with 4alpha-Phorbol 12,13-didecanoate
Method: EM (single particle) / Resolution: 3.41 Å

EMDB-29030: Cryo-EM structure of the human TRPV4 - RhoA in complex with GSK2798745, TRPV4 focused refinement map
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-29031: Cryo-EM structure of the human TRPV4 - RhoA in complex with GSK2798745, RhoA focused refinement map
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-29331: Cryo-EM structure of the human TRPV4 in complex with GSK1016790A, TRPV4 focused refinement map
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-29332: Cryo-EM structure of the human TRPV4 in complex with GSK1016790A, RhoA focused refinement map
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-XPW:
1-({(5S,7S)-3-[5-(2-hydroxypropan-2-yl)pyrazin-2-yl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl}methyl)-1H-benzimidazole-6-carbonitrile

ChemComp-MG:
Unknown entry

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

ChemComp-XQ3:
N-[(2S)-1-{4-[N-(2,4-dichlorobenzene-1-sulfonyl)-L-seryl]piperazin-1-yl}-4-methyl-1-oxopentan-2-yl]-1-benzothiophene-2-carboxamide

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-XS9:
(1aR,1bS,4aS,7aS,7bS,8R,9R,9aS)-9a-(decanoyloxy)-4a,7b-dihydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-5-oxo-1a,1b,4,4a,5,7a,7b,8,9,9a-decahydro-1H-cyclopropa[3,4]benzo[1,2-e]azulen-9-yl decanoate

ChemComp-GSP:
5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN/Hydrolase / TRPV4 / RhoA / GSK2798745 / MEMBRANE PROTEIN / MEMBRANE PROTEIN-Hydrolase complex / GSK1016790A / 4alpha-Phorbol 12 / 13-didecanoate / 4a-PDD

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