A PIP2 Binding Site on a Human TRP Channel: Simulation Studies of PKD2

Abstract

Polycystin-2 (PKD2) is a member of the transient receptor potential (TRP) superfamily of non-selective cation channels. Mutations in this channel and homologous channels lead to a common genetic disease, autosomal dominant polycystic kidney disease (ADPKD). Phosphatidylinositol (4,5) bisphosphate (PIP2) suppresses epidermal growth factor induced PKD2 activation, and hydrolysis of PIP2 can release this inhibition1, suggesting PIP2 may be a modulator of PKD2 channels. Using multi-scale molecular dynamics simulations based on a recent electron cryo-microscopy (cryo-EM) structure of PKD2 (PDB ID: 5K47) we revealed a potential PIP2 binding site between S3, S4 and S5 transmembrane helices. This binding site is close to the vanilloid/lipid-binding site observed in the TRPV1 channel (PDB ID: 5RIZ). Free energy profiles for the interaction of PIP2, phosphatidylserine (PS) and of phosphatidylcholine (PC) with PKD2 support the existence of a discrete binding site, which has a strong selectivity for PIP2 binding. Close examination of the protein-lipid interaction at the lowest-energy binding distance showed that the head group of PIP2 is coordinated by a cluster of basic residues, which are all highly conserved. This suggests that the binding site may play a key role in lipid-mediated modulation of PKD2 channel activity. (1) Ma, R., Li, W., Rundle, D., Kong, J., Akbarali, H. I., and Tsiokas, L. (2005) Mol. Cell. Biol.25, 8285–8298.