Abstract
Precise regulation of calcium homeostasis is essential for many physiological functions. The Ca2+-selective transient receptor potential (TRP) channels TRPV5 and TRPV6 play vital roles in calcium homeostasis as Ca2+ uptake channels in epithelial tissues. Detailed structural bases for their assembly and Ca2+ permeation remain obscure. Here we report the crystal structure of rat TRPV6 at 3.25 Å resolution. The overall architecture of TRPV6 reveals shared and unique features compared with other TRP channels. Intracellular domains engage in extensive interactions to form an intracellular ‘skirt’ involved in allosteric modulation. In the K+ channel-like transmembrane domain, Ca2+ selectivity is determined by direct coordination of Ca2+ by a ring of aspartate side chains in the selectivity filter. On the basis of crystallographically identified cation-binding sites at the pore axis and extracellular vestibule, we propose a Ca2+ permeation mechanism. Our results provide a structural foundation for understanding the regulation of epithelial Ca2+ uptake and its role in pathophysiology.
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Acknowledgements
We thank E. C. Twomey and J. M. Sampson for comments on the manuscript, members of the E. C. Greene laboratory for assistance with their fluorimeter, and the Columbia Protein Core facility for assistance with isothermal titration calorimetry (ITC) measurements. We also thank the personnel at beamlines 24-ID-C/E of APS, X25/X29 of NSLS and 5.0.1/5.0.2 of ALS. This work was supported by National Institutes of Health grants R01 NS083660 (A.I.S.) and T32 GM008281 (K.S.), by a Pew Scholar Award in Biomedical Sciences, a Schaefer Research Scholar Award, a Klingenstein Fellowship Award in the Neurosciences and an Irma T. Hirschl Career Scientist Award (A.I.S.).
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K.S., A.K.S., M.V.Y. and A.I.S. designed the project. K.S., A.K.S. and M.V.Y. performed the experiments. K.S., A.K.S., M.V.Y. and A.I.S. wrote the manuscript.
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Extended data figures and tables
Extended Data Figure 1 Functional characterization of wild-type rat TRPV6 and TRPV6cryst.
a, b, d, e, g, h, Representative ratiometric fluorescence measurements for HEK cells expressing wild-type rat TRPV6 (a, d, g) or TRPV6cryst (b, e, h). Arrows indicate the time at which the corresponding ion was added. After resuspending the cells in nominally calcium-free buffer, addition of Ca2+ (a, b) or Ba2+ (d, e) resulted in robust concentration-dependent increase in Fura-2 signal for both wild-type rat TRPV6 and TRPV6cryst. In contrast, pre-incubation of cells with increasing concentrations of Gd3+ resulted in concentration-dependent reduction in Fura-2 signal for both wild type (g) and TRPV6cryst (h), consistent with Gd3+ inhibition of wild-type TRPV6 demonstrated previously using 45Ca2+ uptake measurements27. c–f, Dose–response curves for Ca2+ (c) and Ba2+ (f) permeation calculated for wild type (blue) and TRPV6cryst (red) (n = 3 for all measurements). The changes in the fluorescence intensity ratio at 340 and 380 nm (F340/F380) were normalized to their approximated maximal values at saturating concentrations of Ca2+ or Ba2+, respectively. The apparent values of half-maximum effective concentration (EC50) for TRPV6cryst (1.70 ± 0.26 mM for Ca2+ and 1.27 ± 0.67 mM for Ba2+) are similar to wild type (1.47 ± 0.80 mM for Ca2+ and 1.91 ± 0.74 mM for Ba2+). i, Dose–response curves for Gd3+ inhibition calculated for wild type (blue) and TRPV6cryst (red) (n = 3 for all measurements). The changes F340/F380 evoked by addition of 2 mM Ca2+ after pre-incubation with various concentrations of Gd3+ were normalized to the maximal change in F340/F380 after addition of 2 mM Ca2+ in the absence of Gd3+. The apparent values of half-maximum inhibitory concentration (IC50) for wild type (3.87 ± 0.83 μM) are comparable to TRPV6cryst (2.57 ± 0.28 μM). Overall, the mutations introduced to crystallize TRPV6 did not significantly alter its cation permeation and inhibition properties. The absence of time-dependent decay of the Fura-2 AM signal in the case of TRPV6cryst is presumably due to its C-terminal truncation, which eliminated a calmodulin-binding site involved in Ca2+-dependent inactivation of TRPV6 (ref. 46). Error bars, s.e.m.
Extended Data Figure 2 Electron density.
a, Stereo view of 2Fo − Fc electron density map (blue mesh, 45–3.25 Å, 1.0σ) superimposed onto a ribbon model for the entire TRPV6cryst monomer. b–g, Close-up views of the 2Fo − Fc map for various portions of TRPV6cryst model, with side chains shown in stick representation. In e, two diagonally opposed subunits are shown to clarify the position of the central pore axis, and the bound Ca2+ ion is shown as a green sphere. In f, inset shows expanded view of the boxed region, demonstrating electron density for connectivity in the S6-TRP helix linker that is distinct from other TRP channel structures14,16,17.
Extended Data Figure 3 Anomalous difference Fourier maps for sulfur and selenium.
a–c, Fragments of the TRPV6cryst model (yellow ribbon) superimposed onto anomalous difference Fourier maps from X-ray diffraction data collected at 1.75 Å from crystals grown in 10 mM Ca2+ (cyan mesh, 38–4.59 Å, 3.0σ) and at 0.979 Å from selenomethionine-labelled crystals (pink mesh, 30–5.00 Å, 3.2σ) of TRPV6cryst. Anomalous signal collected from a selenomethionine–labelled crystal of TRPV6cryst with L630M substitution (a, green mesh, 30–7.20 Å, 3.2σ) was used to aid registry in the C-terminal β3 strand. Domains are labelled in blue. Cysteine and methionine residues are shown as sticks and labelled. Sulfur anomalous difference peaks were observed for all cysteines in the TRPV6cryst model. Selenium anomalous difference peaks were observed for all methionines in the model, except for M480 and M484 in S5, presumably because of flexibility.
Extended Data Figure 4 Comparison of TRPV6cryst and TRPV1.
a, Bottom-up view of TRPV6cryst (blue) and TRPV1 (salmon) tetramers, with ankyrin repeat domain and linker domain helices shown as cylinders. When S1–S4 domains are aligned, as shown, the cytoplasmic skirt of TRPV6 is rotated clockwise with respect to the cytoplasmic skirt of TRPV1. b, Side view of TRPV6cryst (blue) and TRPV1 (salmon) monomers with S1–S4 domain based alignment. The ankyrin repeat domain of TRPV1 extends slightly further into the cytoplasm than TRPV6cryst. c, Alignment of TRPV6cryst (blue) and TRPV1 (salmon) transmembrane domains. Adjacent S1–S4 and pore domains are shown for comparison. Similar to TRPV1, aromatic residues pack against each other to immobilize the TRPV6cryst S1–S4 domain core (shown as sticks). The absence of curvature in S5 and the long extracellular S1–S2 loop protruding towards the pore are distinct features of the TRPV6cryst transmembrane domain. d, Alignment of the TRPV6cryst TRP helix, C-terminal hook and three stranded β-sheet with homologous domains in the TRPV1. Conserved residues (Extended Data Fig. 7) are shown in stick representation.
Extended Data Figure 5 Cysteine crosslinking at the intracellular skirt interface and putative desthiobiotin-binding site at the intracellular intersubunit interface.
a, The TRPV6cryst tetramer with each subunit coloured differently (top) and expanded view of boxed region (bottom), with cysteine-substituted residues shown as sticks. Dashed line and label show Cα–Cα distance. b, SDS–PAGE (4–20% gradient gel) analysis of purified TRPV6 cysteine-substituted mutants in the presence (left) and absence (right) of reducing agent. Cysteines were introduced into a background construct (TRPV6CysKO), in which exposed cysteines in TRPV6cryst were mutated to serine or alanine (C14S, C20S, C70A, C610A and C618A) to prevent non-specific aggregation. Positions corresponding to monomer and tetramer bands are indicated by filled and open triangles, respectively. The appearance of a robust band corresponding to covalently crosslinked tetramer in the D34C–R631C double mutant indicates that the interacting N-terminal helix (which precedes the S1–S4 domain) and β3 strand (which follows the TRP helix) are from different protomers. Taken together with the S6-TRP helix linker connectivity (Extended Data Fig. 2f) that is different from TRPV1/2 (refs 14, 16) and TRPA1 (ref. 17), these data suggest a non-swapped arrangement of the pore and S1–S4 domains; if the canonical domain-swapped arrangement were true, the interacting N-terminal helix and β3 strand would be from the same monomer and no crosslinked high molecular mass species would form. However, in the absence of interpretable density for the S4–S5 linker, we suggest cautious interpretation of this domain arrangement. c, FSEC analysis of purified TRPV6CysKO crosslink mutants in the absence of reducing agent. Each trace shows a single major peak with elution time corresponding to the TRPV6cryst tetramer (black trace). d, e, The putative DTB-binding site is composed of a pocket formed by the N-terminal helix and ankyrin repeats 2–4 of one subunit (blue) and the linker domain of an adjacent subunit (green). DTB is shown as ball and stick, with 2Fo − Fc density shown as grey mesh (45–3.25 Å, 1.0σ). In d, residues that contact DTB are shown as sticks. In e, the binding pocket is shown in surface representation. Interestingly, the DTB-binding site overlaps with the ATP-binding site revealed in the ankryin domain crystal structure of TRPV1 (ref. 47), which was later demonstrated to be conserved in TRPV3 and TRPV4 (ref. 48). The presence of DTB close to this location in TRPV6 corroborates the assertion made in ref. 14 that ligands bound in this region modulate activity by perturbing subunit interactions. Further work is necessary to establish a functional role, if any, of DTB-like compounds on TRPV6 function. f–h, Comparison of the putative DTB-binding site in TRPV6cryst (f) and the ATP-binding site in the crystal structure of the TRPV1 ankyrin domain (g, PDB accession number 2PNN). DTB and ATP are shown in ball and stick. While the ATP-binding site in TRPV1 is shifted towards ankyrin repeat finger 1, both binding sites are located at intersubunit interfaces, as illustrated when the structures are superimposed (h).
Extended Data Figure 6 Comparison of the ion channel pore in TRPV6cryst with other tetrameric ion channels.
a–l, The pore of TRPV6cryst (yellow ribbon) was aligned with TRPV1 (a, PDB accession number 3J5P), NaVAb (b, PDB accession number 3RVY), Slo2.2 (c, PDB accession number 5A6E), TRPA1 (d, PDB accession number 3J9P), KV1.2 (e, PDB accession number 2R9R), KcsA (f, PDB accession number 1BL8), InsP3R1 (g, PDB accession number 3JAV), RyR1 (h, PDB accession number 3J8H), NaVRh (i, PDB accession number 4DXW), CaVAb (j, PDB accession number 4MVM), CaV1.1 domains I and III (k, PDB accession number 3JBR) and CaV1.1 domains II and IV (l, PDB accession number 3JBR). In each of the alignments, acidic residues located at or close to the selectivity filter region are shown as sticks for comparison. Notably, structures of Ca2+-permeable channels (a, d, g, h, j–l) display a high concentration of acidic residues in the outer pore region. In a–c, methionine residues close to the S6 bundle crossing are shown as sticks. Notably, the methionine at the lower gate points away from the pore in TRPV1 (a), despite high sequence conservation in this region among TRPV channels (Extended Data Fig. 7). In Slo2.2 (b) and NaVAb (c), methionine side chains occlude the lower gate as in TRPV6cryst, indicating that the closed conformation of the lower gate can be chemically similar for Na+-, K+- and Ca2+-selective channels. m–o, Comparison of calcium-binding sites in TRPV6cryst (m), the engineered voltage gated Ca2+ channel CaVAb (n) and the putative Ca2+ site in Cav1.1 (o, domains I and III are shown). Residues constituting the selectivity filters are shown in stick representation. Ca2+ ions are shown as green spheres. Sites 1 and 2 from TRPV6cryst overlap with the positions of sites 1 and 3 from CaVAb, respectively. While it has been proposed that, owing to electrostatic repulsion, sites 1, 2 and 3 cannot be simultaneously occupied in CaVAb, distances between Ca2+-binding sites in TRPV6cryst are sufficiently large such that they can be simultaneously occupied. The putative Ca2+ site in CaV1.1 is near the equivalent location of site 2 in CaVAb.
Extended Data Figure 7 Sequence alignment of rat TRPV subtypes.
Secondary structure elements are depicted above the sequence as cylinders (α-helices), arrows (β-strands) and lines (loops). Dashed lines show residues in the TRPV6cryst construct not included in the TRPV6cryst structural model. Red boxes and a red arrow highlight substitution mutations and the C-terminal truncation point in TRPV6cryst, respectively (see Methods). The ¥ symbol marks the N-linked glycosylation site in the extracellular loop connecting S1 and S2 conserved in TRPV6 (and TRPV5) channels. The thick red line marks the location of the selectivity filter.
Extended Data Figure 8 Isothermal titration calorimetry analysis of TRPV6 interaction with Gd3+ and anomalous peak amplitudes.
a, Gd3+ in the syringe (700 μM) was titrated into TRPV6 (6.38 μM) loaded into the cell. Measurements were performed at 25 °C. Top, the raw data for nineteen 2-μl injections of Gd3+. The area of each injection peak is equal to the total heat released from that injection. Bottom, the integrated heat per injection versus molar ratio. Binding of Gd3+ to TRPV6 was analysed using models with one and two types of binding site. A model with one type of binding site was not sufficient to explain the binding isotherm (blue line). In contrast, analyses of the binding isotherm using the model with two types of binding site, according to equation Qitot = V0Mtot((n1ΔH1K1[X]/(1 + K1[X])) + (n2ΔH2K2[X]/(1 + K2[X]))), where Qitot is total heat after the ith injection, V0 is the volume of calorimetric cell, Mtot is the bulk concentration of protein, [X] is the free concentration of Gd3+, n1 and n2 are the numbers of type 1 and 2 sites, K1 and K2 are the observed equilibrium constants for each type of the sites and ∆H1 and ∆H2 are the corresponding enthalpy changes, satisfactorily described the data (red line), and the corresponding values of thermodynamic parameters are given in b. The values of ΔG and TΔS were calculated using the following relationships: ΔG = −RT lnK and ΔG = ΔH − TΔS. b, Table showing the parameters of experimental data fitting to the model with two types of Gd3+-binding site. The straightforward interpretation of the ITC results is that the ITC type 1 (n ≈ 1) and type 2 (n ≈ 4) sites represent the main (site 1) and recruitment sites identified crystallographically (Fig. 4e, f). Correspondingly, the affinity to Gd3+ for recruitment sites is ~10 times lower than for site 1. c, Table showing anomalous peak amplitudes in σ calculated from data collected for Ca2+ (38–4.59 Å), Ba2+ (38–4.59 Å) and Gd3+ (38–4.59 Å). No numbers are given if the peaks were not observed.
Extended Data Figure 9 Crystal lattice contact of TRPV6cryst.
a, b, Two views of TRPV6cryst crystal packing in the P4212 space group. A single TRPV6cryst protomer in the asymmetric unit is shown in blue. c, d, Close-up views of boxed region in a. Contacting residues are shown in stick, and Cα–Cα distances are labelled in d. The crystal contact is apparently mediated by cation-π and/or hydrogen bonding interactions between these residues. Crystals in the P4212 space group did not form when the native isoleucine was present at position 62.
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Saotome, K., Singh, A., Yelshanskaya, M. et al. Crystal structure of the epithelial calcium channel TRPV6. Nature 534, 506–511 (2016). https://doi.org/10.1038/nature17975
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DOI: https://doi.org/10.1038/nature17975
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