The Structural Basis of Calcium-Dependent Inactivation of the Transient Receptor Potential Vanilloid 5 Channel

Area of Science:

• Biochemistry
• Molecular Biology
• Physiology

Background:

• The transient receptor potential vanilloid channel subfamily member 5 (TRPV5) is crucial for kidney calcium reabsorption and homeostasis.
• Calmodulin (CaM) regulates TRPV5 activity via binding to its C-terminus, forming a negative feedback mechanism.

Purpose of the Study:

• To characterize the TRPV5 C-terminal CaM binding site and its interaction with CaM at an atomistic level.
• To elucidate the structural basis of Ca²⁺/CaM-dependent TRPV5 regulation.

Main Methods:

• De novo solution structure determination of the TRPV5 C-terminus in complex with a CaM mutant.
• Structural analysis under basal and elevated calcium conditions.

Main Results:

• At basal calcium, TRPV5 C-terminus exclusively binds the CaM C-lobe, leaving the N-lobe conformationally free.
• At elevated calcium, TRPV5 C-terminus binds both CaM N- and C-lobes, forming a tight 1:1 complex.
• The CaM N-lobe acts as the calcium sensor, mediating channel inactivation.

Conclusions:

• The study provides atomistic insights into the Ca²⁺/CaM-dependent regulation of TRPV5.
• Findings support a novel model for Ca²⁺/CaM-mediated inactivation of TRPV channels.
• This mechanism is critical for maintaining calcium homeostasis in the kidney.