Abstract
Calcium is the most abundant metal in the human body that plays vital roles as a cellular electrolyte as well as the smallest and most frequently used signaling molecule. Calcium uptake in epithelial tissues is mediated by tetrameric calcium-selective transient receptor potential (TRP) channels TRPV6 that are implicated in a variety of human diseases, including numerous forms of cancer. We used TRPV6 crystal structures as templates for molecular dynamics simulations to identify ion binding sites and to study the permeation mechanism of calcium and other ions through TRPV6 channels. We found that at low Ca2+ concentrations, a single calcium ion binds at the selectivity filter narrow constriction formed by aspartates D541 and allows Na+ permeation. In the presence of ions, no water binds to or crosses the pore 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 tightly, blocks the channel and prevents Na+ from permeating the pore. Our results provide structural foundations for understanding permeation and block in tetrameric calcium-selective ion channels.
Highlights
Ion channels in biological membranes conduct ions with speeds approaching diffusion limit[1]
Equilibrium molecular dynamics (MD) simulations of the TRPV6 channel were performed in conditions closely related to the physiological, i.e. at room temperature and in presence of the lipid membrane, water and ions
Equilibrium MD trajectories of TRPV6 in its Apo form and in presence of ions Ca2+, Ba2+ or Gd3+ were initiated with the protein and ion coordinates determined by the corresponding crystal structures (PDB IDs: 5IWK, 5IWP, 5IWR and 5IWT)
Summary
Ion channels in biological membranes conduct ions with speeds approaching diffusion limit (often faster than 106 ions per second)[1]. We have recently solved the first crystal structures of a eukaryotic tetrameric calcium-selective ion channel TRPV636 that plays a vital role in calcium homeostasis as a Ca2+ uptake channel in epithelial tissues and is implicated in a variety of human diseases, including cancers[48,49,50,51,52,53,54,55,56]. These structures resolve the ion channel selectivity filter in the presence of several ions, including Ca2+, Ba2+ and Gd3+ and represent the first naturally occurring molecular template of a calcium specific tetrameric channel that can be analyzed to develop the mechanism of calcium permeation and understand calcium selectivity in Ca2+ channels. Our findings set firm ground to describe principles of calcium selectivity in tetrameric ion channels and create foundations for future modeling studies
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