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      Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2

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          Summary

          Polycystin-2 (PC2) is a transient receptor potential (TRP) channel present in ciliary membranes of the kidney. PC2 shares a transmembrane fold with other TRP channels, in addition to an extracellular domain found in TRPP and TRPML channels. Using molecular dynamics (MD) simulations and cryoelectron microscopy we identify and characterize PIP 2 and cholesterol interactions with PC2. PC2 is revealed to have a PIP binding site close to the equivalent vanilloid/lipid binding site in the TRPV1 channel. A 3.0-Å structure reveals a binding site for cholesterol on PC2. Cholesterol interactions with the channel at this site are characterized by MD simulations. The two classes of lipid binding sites are compared with sites observed in other TRPs and in Kv channels. These findings suggest PC2, in common with other ion channels, may be modulated by both PIPs and cholesterol, and position PC2 within an emerging model of the roles of lipids in the regulation and organization of ciliary membranes.

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          Highlights

          • Lipid interactions of PC2 channels have been explored by MD simulation and cryo-EM

          • PIP 2 binds to a site corresponding to the vanilloid/lipid binding site of TRPV1

          • Cholesterol binds between the S3 and S4 helices and S6 of the adjacent subunit

          • PC2, in common with other channels, may be modulated by PIPs and cholesterol

          Abstract

          Wang et al. use molecular dynamics simulations and cryoelectron microscopy to explore interactions of the PC2 channel with lipids. Phosphatidylinositol phosphates (PIPs) bind to a site corresponding to the vanilloid/lipid binding site of TRPV1, whereas cholesterol binds to a different site. This suggests PC2 may be modulated by PIPs and cholesterol.

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          Most cited references86

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          TRP channels.

          The TRP (Transient Receptor Potential) superfamily of cation channels is remarkable in that it displays greater diversity in activation mechanisms and selectivities than any other group of ion channels. The domain organizations of some TRP proteins are also unusual, as they consist of linked channel and enzyme domains. A unifying theme in this group is that TRP proteins play critical roles in sensory physiology, which include contributions to vision, taste, olfaction, hearing, touch, and thermo- and osmosensation. In addition, TRP channels enable individual cells to sense changes in their local environment. Many TRP channels are activated by a variety of different stimuli and function as signal integrators. The TRP superfamily is divided into seven subfamilies: the five group 1 TRPs (TRPC, TRPV, TRPM, TRPN, and TRPA) and two group 2 subfamilies (TRPP and TRPML). TRP channels are important for human health as mutations in at least four TRP channels underlie disease.
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            Structure of the TRPV1 ion channel determined by electron cryo-microscopy

            Transient receptor potential (TRP) channels are sensors for a wide range of cellular and environmental signals, but elucidating how these channels respond to physical and chemical stimuli has been hampered by a lack of detailed structural information. Here, we exploit advances in electron cryo-microscopy to determine the structure of a mammalian TRP channel, TRPV1, at 3.4Å resolution, breaking the side-chain resolution barrier for membrane proteins without crystallization. Like voltage-gated channels, TRPV1 exhibits four-fold symmetry around a central ion pathway formed by transmembrane helices S5–S6 and the intervening pore loop, which is flanked by S1–S4 voltage sensor-like domains. TRPV1 has a wide extracellular ‘mouth’ with short selectivity filter. The conserved ‘TRP domain’ interacts with the S4–S5 linker, consistent with its contribution to allosteric modulation. Subunit organization is facilitated by interactions among cytoplasmic domains, including N-terminal ankyrin repeats. These observations provide a structural blueprint for understanding unique aspects of TRP channel function.
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              TRPV1 structures in distinct conformations reveal mechanisms of activation

              TRP channels are polymodal signal detectors that respond to a wide range of physical and chemical stimuli. Elucidating how these channels integrate and convert physiological signals into channel opening is essential to understanding how they regulate cell excitability under normal and pathophysiological conditions. Here we exploit pharmacological probes (a peptide toxin and small vanilloid agonists) to determine structures of two activated states of the capsaicin receptor, TRPV1. A domain (S1-S4) that moves during activation of voltage-gated channels remains stationary in TRPV1, highlighting differences in gating mechanisms for these structurally related channel superfamilies. TRPV1 opening is associated with major structural rearrangements in the outer pore, including the pore helix and selectivity filter, as well as pronounced dilation of a hydrophobic constriction at the lower gate, suggesting a dual gating mechanism. Allosteric coupling between upper and lower gates may account for rich physiologic modulation exhibited by TRPV1 and other TRP channels.
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                Author and article information

                Contributors
                Journal
                Structure
                Structure
                Structure(London, England:1993)
                Cell Press
                0969-2126
                1878-4186
                04 February 2020
                04 February 2020
                : 28
                : 2
                : 169-184.e5
                Affiliations
                [1 ]Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
                [2 ]Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
                [3 ]UCB Pharma, 208 Bath Road, Slough SL1 3WE, UK
                Author notes
                []Corresponding author liz.carpenter@ 123456sgc.ox.ac.uk
                [∗∗ ]Corresponding author mark.sansom@ 123456bioch.ox.ac.uk
                [4]

                Present address: D. E. Shaw Research, 120 W. 45th St., 39th Fl., New York, NY 10036, USA

                [5]

                Present address: Visterra, Inc., 275 2nd Avenue, 4th Floor, Waltham, MA 02451, USA

                [6]

                Lead Contact

                Article
                S0969-2126(19)30389-2
                10.1016/j.str.2019.11.005
                7001106
                31806353
                69ab2f67-e7b2-4e40-996b-b45ec1cc2545
                © 2019 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 June 2019
                : 4 September 2019
                : 8 November 2019
                Categories
                Article

                Molecular biology
                trp channel,lipids,cryoelectron microscopy,molecular dynamics,cholesterol,phosphatidylinositol bisphosphate,polycystin-2

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