Structural insights into TRPV4-Rho GTPase signaling complex function and disease

Area of Science:

• Molecular biology
• Structural biology
• Biophysics

Background:

• Ion channel and small GTPase interactions are vital for cellular functions and disease.
• TRPV4 (transient receptor potential vanilloid 4) is a calcium-permeable channel implicated in various conditions and hereditary neuromuscular diseases.
• Understanding the structural basis of TRPV4's interaction with RhoA is crucial for deciphering its role in health and disease.

Approach:

• Utilized cryo-electron microscopy (cryo-EM) to determine high-resolution structures of human TRPV4.
• Captured TRPV4 in complex with RhoA across apo, antagonist-bound closed, and agonist-bound open states.
• Investigated the impact of mutations at the TRPV4-RhoA interface on channel activity.

Key Points:

• Cryo-EM structures reveal the mechanism of ligand-dependent TRPV4 gating and the role of RhoA in constraining channel movement.
• The interaction interface between TRPV4 and RhoA is critical, with disease-associated mutations often found at this site.
• Perturbing the TRPV4-RhoA interface increases TRPV4 channel activity, suggesting a link to disease pathogenesis.

Conclusions:

• The interaction strength between TRPV4 and RhoA modulates calcium homeostasis and actin remodeling.
• Disruption of TRPV4-RhoA interactions contributes to TRPV4-related neuromuscular diseases.
• These findings provide a structural foundation for developing targeted TRPV4 therapeutics.