Ion Permeation Mechanism in Epithelial Calcium Channel TRVP6

trpv6

Based on TRPV6 crystal structures, molecular dynamics simulations predicted binding sites for calcium, barium and gadolinium inside the channel pore. The first TRPV6 crystal structure was solved in our lab in 2015 and published in 2016 in Nature. We succeeded to determine several crystal structures of the channel bound to Ca2+, Ba2+ and Gd3+ and identified ion binding sites in the channel pore as well as in the extracellular vestibule (recruitment sites). Site locations and ion coordination geometry allowed us to make initial assumptions about ion permeation mechanism in TRPV6. It is well known that at low Ca2+ concentrations, the TRPV6-mediated inward current is mainly carried by Na+ ions. An increase in Ca2+ concentration leads to an increase in Ca2+ current but a reduction of Na+ current. We used MD simulations with varying numbers of Ca2+ and Na+ ions to verify experimental observations and to test our structural models.

Briefly, at low Ca2+ concentrations, only a single calcium ion binds at the narrow constriction of the TRPV6 selectivity filter formed by aspartates D541 and allows Na+ permeation. During ion permeation, no water crosses the channel pore narrow constriction. At high Ca2+ concentrations, calcium permeates the pore according to the knock-off mechanism that includes formation of a short-lived transition state with three calcium ions bound near D541. For Ba2+, the transition state lives longer and the knock-off permeation occurs slower. Gd3+ binds at D541 more tightly, blocks the channel and prevents Na+ from permeating the pore.

Check out these cool movies from the paper:

Movie 1. Na+ permeation through TRPV6 channel

Movie 2. Knock-off mechanism of Ca2+ permeation

The work published in Scientific Reports was done in collaboration with Dr. Maria Kurnikova’s lab from Carnegie Mellon University.

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