Study On Regulation Of Kir Channel Gating By Protein Phosphorylation

ROMK2is a subtype of the Inwardly Rectifying Potassium Channels Family and playskey roles in maintaining membrane potential and regulating the secretion of potassium ions.The activity of ROMK2channel is critically dependent on PIP2and regulated by manyother factors, such as magnesium ions, hydrogen ions. Moreover, PKA-Dependentphosphorylation can increase open probability of ROMK2channel the mechanism of whichis still unclear. In this paper, we focused on regulation of the ROMK2gating by thephosphorylation at Sre200through molecular dynamics simulation, molecular docking andTargeted molecular dynamics simulation. We get some valuable results:1. Phosphorylation of Sre200enhances the flexible of two pieces of residues which are52-59and161-168and changes the conformation of side chain of Trp58which iscorresponding to Trp79of Kir2.2.2. The docking results show that conformational change of Trp58makes the bindingdomain of PIP2more favourable to PIP2binding, meaning that phosphorylation at Ser200up-regulating the activity of ROMK2by facilitating PIP2binding with channel.3. The C-terminal domain (CTD) of phosphorylated ROMK2channel shows a2-upward motion which has been shown as necessary conformation change to open thechannel, so phosphorylation cause the move up of CTD is beneficial to increase openprobability of ROMK2channel.4. The interaction between C-linker and CTD of phosphorylated channel are strongerthan that of non-phosphorylated channel which may contribute to the upward transition ofCTD and facilitate to increase the open probability of ROMK2.This work may shed light on the understanding of regulation of ROMK2gating byphosphorylation at other residues.