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Lipid interactions of a ciliary membrane TRP channel: Simulation and structural studies of polycystin-2

DOI: 10.1016/j.str.2019.11.005 DOI Help

Authors: Qinrui Wang (Structural Genomics Consortium, University of Oxford) , Robin A. Corey (University of Oxford) , George Hedger (University of Oxford) , Prafulla Aryal (University of Oxford) , Mariana Grieben (Structural Genomics Consortium, University of Oxford) , Chady Nasrallah (Structural Genomics Consortium, University of Oxford) , Agnese Baronina (University of Oxford) , Ashley C. W. Pike (Structural Genomics Consortium, University of Oxford) , Jiye Shi (UCB Pharma) , Elisabeth P. Carpenter (Structural Genomics Consortium, University of Oxford) , Mark S. P. Sansom (University of Oxford)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Structure

State: Published (Approved)
Published: December 2019
Diamond Proposal Number(s): 14856

Open Access Open Access

Abstract: 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.

Journal Keywords: TRP channel; lipids; cryoelectron microscopy; molecular dynamics; cholesterol; phosphatidylinositol bisphosphate; polycystin-2

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

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