Molecular insights into the structural and dynamical changes of calcium channel TRPV6 induced by its interaction with phosphatidylinositol 4,5-bisphosphate

Abstract

Transient receptor potential vanilloid subfamily member 6 (TRPV6) is an epithelial calcium channel that regulates the initial step of the transcellular calcium transport pathway. TRPV6 is expressed in the kidney, intestine, placenta, and other tissues, and the dysregulation of the channel is implicated in several human cancers. It has been reported that phosphatidylinositol 4,5-bisphosphate (PIP₂) activates TRPV6 and its close homologue TRPV5; however, the underlying molecular mechanism is less clear. Recently, a structure of rabbit TRPV5 in complex with dioctanoyl (diC₈) PIP₂, a soluble form of PIP₂, was determined by cryo-electron microscopy. Based on this structure, the structural model of human TRPV6 with PIP₂ was set up, and then molecular dynamics simulations were performed for TRPV6 with and without PIP₂. Simulation results show that the positively charged residues responsible for TRPV5 binding of diC₈ PIP₂ are conserved in the interactions between TRPV6 and PIP₂. The binding of PIP₂ to TRPV6 increases the distance between the diagonally opposed residues D542 in the selectivity filter and that between the diagonally opposed M578 residues in the lower gate of TRPV6. A secondary structural analysis reveals that residues M578 in TRPV6 undergo structural and position changes during the binding of PIP₂ with TRPV6. In addition, principal component analysis indicates that the binding of PIP₂ increases the dynamical motions of both the selectivity filter and the lower gate of TRPV6. These changes induced by PIP₂ favor the channel opening. Thus, this study provides a basis for understanding the mechanism underlying the PIP₂-induced TRPV6 channel activation.

Communicated by Ramaswamy H. Sarma

Keywords:

• TRPV6
• Ca²⁺-selective channel
• PIP₂
• selectivity filter
• lower gate
• molecular dynamics

Acknowledgment

We thank the Alabama Supercomputer Center and Supercomputer facility at the University of Alabama at Birmingham for providing computational resources.

Disclosure statement

The authors declare no competing financial interest.

Data availability statement

All data and protocols are available upon request.

Author contributions

Lingyun Wang and Ji-Bin Peng designed the research. Lingyun Wang performed the molecular dynamics simulations and analyzed the data. Lingyun Wang, Ruiqi Cai, Xing-Zhen Chen, and Ji-Bin Peng contributed to writing and editing the manuscript.

Additional information

Funding

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK104924).