Abstract
ATP-sensitive potassium (KATP) channels consist of an inwardly rectifying K+ channel (Kir6.2) pore, to which four ATP-sensitive sulfonylurea receptor (SUR) domains are attached, thereby coupling K+ permeation directly to the metabolic state of the cell. Dysfunction is linked to neonatal diabetes and other diseases. K+ flux through these channels is controlled by conformational changes in the helix bundle region, which acts as a physical barrier for K+ permeation. In addition, the G-loop, located in the cytoplasmic domain, and the selectivity filter might contribute to gating, as suggested by different disease-causing mutations. Gating of Kir channels is regulated by different ligands, like Gβγ, H+, Na+, adenosine nucleotides, and the signaling lipid phosphatidyl-inositol 4,5-bisphosphate (PIP2), which is an essential activator for all eukaryotic Kir family members. Although molecular determinants of PIP2 activation of KATP channels have been investigated in functional studies, structural information of the binding site is still lacking as PIP2 could not be resolved in Kir6.2 cryo-EM structures. In this study, we used Molecular Dynamics (MD) simulations to examine the dynamics of residues associated with gating in Kir6.2. By combining this structural information with functional data, we investigated the mechanism underlying Kir6.2 channel regulation by PIP2.
Highlights
Rectifying K+ (Kir) channels are expressed in diverse tissues and regulate physiological processes by setting the cellular resting membrane potential
Even though recent studies suggest that partially dehydrated K+ ions can pass the helix bundle crossing (HBC) gate formed by aromatic side chains (Bernsteiner et al, 2019; Black et al, 2020), the constrictions at sites 1 and 3 are formed by hydrophobic residues, rendering K+ passage very unlikely
Combined with the previous observation that a salt bridge between ATP and K39 is broken in the presence of PIP2, which subsequently leads to a rotation of the K39 amine group towards the PIP2 head group (Pipatpolkai et al, 2021), this might suggest the following order of gating transition events: In a first step, PIP2 binding competes with ATP for coordination of the amine group of K39
Summary
Rectifying K+ (Kir) channels are expressed in diverse tissues and regulate physiological processes by setting the cellular resting membrane potential. X-ray and cryo-EM structures of several different Kir family members are available, revealing a remarkably conserved pore architecture, despite widely different ligand gating mechanisms. Gating of Kir and Kir4/5 channels is controlled by pH, Kir channels are regulated by Gβγ proteins, and Kir by ADP/ATP and sulfonylurea receptor subunits (Nichols and Lopatin 1997). Recent cryo-EM structures of KATP channels (Martin et al, 2017a; Martin et al, 2017b; Lee et al, 2017; Li et al, 2017; Wu et al, 2018; Ding et al, 2019) provide important progress towards understanding the complex gating regulation of this important subfamily, which couples the metabolic state of a cell to its electrical excitability (Hibino et al, 2010; Rorsman and Ashcroft 2018). Like in Kir and Kir channels, the pore below the selectivity filter (SF) is lined by two main constrictions: the so-called
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