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

• Published in: Structure (London) 2020-02, Vol.28 (2), p.169-184.e5
• Main Authors: Wang, Qinrui, Corey, Robin A., Hedger, George, Aryal, Prafulla, Grieben, Mariana, Nasrallah, Chady, Baronina, Agnese, Pike, Ashley C.W., Shi, Jiye, Carpenter, Elisabeth P., Sansom, Mark S.P.
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; cholesterol; Cholesterol - metabolism; Cryoelectron Microscopy; Humans; lipids; Models, Molecular; molecular dynamics; Molecular Dynamics Simulation; phosphatidylinositol bisphosphate; Phosphatidylinositol Phosphates - metabolism; polycystin-2; Protein Binding; Protein Structure, Secondary; Sf9 Cells; TRP channel; TRPP Cation Channels - chemistry; TRPP Cation Channels - metabolism
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2019.11.005

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 PIP2 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. [Display omitted] •Lipid interactions of PC2 channels have been explored by MD simulation and cryo-EM•PIP2 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 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.