KIRPAS · Structural characterization of a Kir potassium channel and its involvement in Andersen’s syndrome

Structural characterization of a Kir potassium channel and its involvement in Andersen’s syndrome

Kir2.1 channels are integral membrane proteins that selectively control the permeation of K+ ions across cell membranes. This K+ flow is essential for many physiological processes, including maintaining the electrical stability of cells, especially in the heart and muscles. The opening and closing of these channels, a process known as gating, is modulated by a molecule called PIP2 (phosphatidylinositol 4,5-bisphosphate). However, the description of the way in which PIP2 induces the structural changes in Kir2.1 channels to control the gating mechanism remains poorly understood. This lack of understanding is significant because defects in the Kir2.1 channels are linked to several human diseases, including Andersen-Tawil syndrome (ATS), a genetic disorder that can lead to episodes of muscle weakness and paralysis, and abnormal heart rhythms. Despite the known connection between Kir2.1 mutations and ATS, it is not yet clear how these mutations impact the Kir2.1 channel structure and disrupt the normal function of these channels. The primary objective of this project is to uncover how Kir2.1 channels function at atomic level, both in their normal state and when affected by ATS-related mutations. This project successfully determined two high-resolution structures using cryo-EM of human Kir2.1 in the absence of PIP2, each in a different conformation. The first structure was obtained using a Kir2.1 sample in the presence of DDM detergent and captured the Kir2.1 channel in an extended, closed and non-conductive state and provided insights into its mechanism of function. The second structure, obtained using a Kir2.1 sample in the presence of amphipols, revealed the channel in a compact conformation, but in an inhibited or poorly activated state. Moreover, by combining electrophysiological experiments, cryo-EM analysis and molecular dynamics simulations, this project identified the molecular mechanisms by which two ATS-causing mutations (R312H and C154Y) impact Kir2.1 channel function.

Data: CORDIS, © European Union