PT  - JOURNAL ARTICLE
AU  - Qinrui Wang
AU  - George Hedger
AU  - Prafulla Aryal
AU  - Mariana Grieben
AU  - Chady Nasrallah
AU  - Agnese Baronina
AU  - Ashley C.W. Pike
AU  - Jiye Shi
AU  - Elisabeth P. Carpenter
AU  - Mark S.P. Sansom
TI  - Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2 (PC2)
AID  - 10.1101/589515
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 589515
4099  - http://biorxiv.org/content/early/2019/03/26/589515.short
4100  - http://biorxiv.org/content/early/2019/03/26/589515.full
AB  - Polycystin-2 (PC2) is a member of the TRPP subfamily of TRP channels and is present in ciliary membranes of the kidney. PC2 can be either homo-tetrameric, or heterotetrameric with PC1. PC2 shares a common transmembrane fold with other TRP channels, in addition to having a novel extracellular domain. Several TRP channels have been suggested to be regulated by lipids, including phosphatidylinositol phosphates (PIPs). We have combined molecular dynamics simulations with cryoelectron microscopy to explore possible lipid interactions sites on PC2. We propose that PC2 has a PIP-binding site close to the equivalent vanilloid/lipid-binding site in the TRPV1 channel. A 3.0 Å cryoelectron microscopy map reveals a binding site for cholesterol on PC2. Cholesterol interactions with the channel at this site are further characterized by MD simulations. These results help to position PC2 within an emerging model of the complex roles of lipids in the regulation and organization of ciliary membranes.