Structural Insights into ATP-Sensitive Potassium Channel Mechanics: A Role of Intrinsically Disordered Regions

Abstract

Commonly used techniques, such as CryoEM or X-ray, are not able to capture the structural reorganizations of disordered regions of proteins (IDR); therefore, it is difficult to assess their functions in proteins based exclusively on experiments. To fill this gap, we used computational molecular dynamics (MD) simulation methods to capture IDR dynamics and trace biological function-related interactions in the Kir6.2/SUR1 potassium channel. This ATP-sensitive octameric complex, one of the critical elements in the insulin secretion process in human pancreatic β-cells, has four to five large, disordered fragments. Using unique MD simulations of the full Kir6.2/SUR1 channel complex, we present an in-depth analysis of the dynamics of the disordered regions and discuss the possible functions they could have in this system. Our MD results confirmed the crucial role of the N-terminus of the Kir6.2 fragment and the L0-loop of the SUR1 protein in the transfer of mechanical signals between domains that trigger insulin release. Moreover, we show that the presence of IDRs affects natural ligand binding. Our research takes us one step further toward understanding the action of this vital complex.

Molecular Dynamics Simulation of Kir6.2 Variants Reveals Potential Association with Diabetes Mellitus

“…Kir6.2 N-terminal fragment and the SUR1 protein L0-loop has been shown in the signal transfer that stimulates the release of insulin [23]. Genetic mutations in the genes that encode KATP channel subunits can result in metabolic and neuronal diseases [24].…”

“…They report that the Kir6.2 mutation L164P changes the geometry and stability of the K ATP channel and is implicated in NDM [15]. In addition, using MD simulations, the important role of the Kir6.2 N-terminal fragment and the SUR1 protein L0-loop has been shown in the signal transfer that stimulates the release of insulin [23]. Genetic mutations in the genes that encode K ATP channel subunits can result in metabolic and neuronal diseases [24].…”

Sulfonylurea receptor 2 (SUR2), intricate sensors for intracellular Mg‐nucleotides

“…Although the NBD1‐TMD2 linker of SUR1 might have certain helical structures as suggested by MD‐simulation (the 900‐loop in ref. [40]), SUR1 in humans lacks a functional R helix due to the lack of conservation of key amino acids that are important for the inhibitory function of the R helix (Figure 2D). [ 37 ] To investigate the evolutionary origins of the R helix, we performed a sequence alignment of SUR genes in several animals.…”