A Cholesterol Dimer Stabilizes the Inactivated State of an Inward-Rectifier Potassium Channel

Cholesterol oligomers reside in multiple membrane protein X-ray crystal structures. Yet, there is no direct link between these oligomers and a biological function. Here we present the structural and functional details of a cholesterol dimer that stabilizes the inactivated state of an inward-rectifier potassium channel KirBac1.1. K+ efflux assays confirm that high cholesterol concentration reduces K+ conductance. We then determine the structure of the cholesterol-KirBac1.1 complex using Xplor-NIH simulated annealing calculations driven by solid-state NMR distance measurements. These calculations identified an alpha-alpha cholesterol dimer docked to a cleft formed by adjacent subunits of the homotetrameric protein. We compare these results to coarse grain molecular dynamics simulations. This is one of the first examples of a cholesterol oligomer performing a distinct biological function and structural characterization of a conserved promiscuous lipid binding region.

Automated summary

Cholesterol oligomers are found in various membrane protein crystal structures, but their biological function is not well understood. This study presents the structural and functional details of a cholesterol dimer that stabilizes the inactivated state of an inward-rectifier potassium channel. The findings provide insights into the role of cholesterol oligomers in regulating channel conductance.