Role for SUR2A ED domain in allosteric coupling within the K_ATP channel complex

Allosteric regulation of heteromultimeric ATP-sensitive potassium (K _ATP) channels is unique among protein systems as it implies transmission of ligand-induced structural adaptation at the regulatory SUR subunit, a member of ATP-binding cassette ABCC family, to the distinct pore-forming K⁺ (Kir6.x) channel module. Cooperative interaction between nucleotide binding domains (NBDs) of SUR is a prerequisite for K _ATP channel gating, yet pathways of allosteric intersubunit communication remain uncertain. Here, we analyzed the role of the ED domain, a stretch of 15 negatively charged aspartate/glutamate amino acid residues (948-962) of the SUR2A isoform, in the regulation of cardiac K_ATP channels. Disruption of the ED domain impeded cooperative NBDs interaction and interrupted the regulation of K_ATP channel complexes by MgADP, potassium channel openers, and sulfonylurea drugs. Thus, the ED domain is a structural component of the allosteric pathway within the K_ATP channel complex integrating transduction of diverse nucleotide-dependent states in the regulatory SUR subunit to the open/closed states of the K ⁺-conducting channel pore.