Calcium-selective transient receptor potential vanilloid subfamily member 6 (TRPV6) channels play a critical role in calcium uptake in epithelial tissues1,2,3,4. Altered TRPV6 expression is associated with a variety of human diseases5, including cancers6. TRPV6 channels are constitutively active1,7,8 and their open probability depends on the lipidic composition of the membrane in which they reside; it increases substantially in the presence of phosphatidylinositol 4,5-bisphosphate7,9. Crystal structures of detergent-solubilized rat TRPV6 in the closed state have previously been solved10,11. Corroborating electrophysiological results3, these structures demonstrated that the Ca2+ selectivity of TRPV6 arises from a ring of aspartate side chains in the selectivity filter that binds Ca2+ tightly. However, how TRPV6 channels open and close their pores for ion permeation has remained unclear. Here we present cryo-electron microscopy structures of human TRPV6 in the open and closed states. The channel selectivity filter adopts similar conformations in both states, consistent with its explicit role in ion permeation. The iris-like channel opening is accompanied by an α-to-π-helical transition in the pore-lining transmembrane helix S6 at an alanine hinge just below the selectivity filter. As a result of this transition, the S6 helices bend and rotate, exposing different residues to the ion channel pore in the open and closed states. This gating mechanism, which defines the constitutive activity of TRPV6, is, to our knowledge, unique among tetrameric ion channels and provides structural insights for understanding their diverse roles in physiology and disease.
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We thank T. Rohacs for advice on electrophysiological recordings, J. Frank for comments on the manuscript, H. Kao for computational support and members of the E.C. Greene laboratory for assistance with their fluorimeter. L.L.M. and E.C.T. are supported by the NIH (T32 GM008224 and F31 NS093838, respectively). A.I.S. is supported by the NIH (R01 CA206573, R01 NS083660), and Amgen Young Investigator and Irma T. Hirschl Career Scientist awards. Data were collected at the Columbia University Medical Center cryo-EM facility and at the Simons Electron Microscopy Center and National Resource for Automated Molecular Microscopy located at the New York Structural Biology Center, supported by grants from the Simons Foundation (349247), NYSTAR, and the NIH (GM103310).
Extended data figures
Extended data tables
A morph between closed and open states of human TRPV6 represented by the hTRPV6-R470E and wild type hTRPV6 structures, respectively. Shown is the pore domain viewed intracellularly and illustrating the iris-like pore opening or viewed parallel to the membrane, with the front and back subunits disappearing for clarity, and illustrating the α-to-π helical transition in S6 during channel opening. Residues around the gate and critical for permeation aspartates D542 are shown in stick representation.
About this article
Nature Communications (2018)