SUR domains that associate with and gate KATP pores define a novel gatekeeper

Structure-function analyses of K+ channels identify a common pore architecture whose gating depends on diverse signal sensing elements. The gatekeepers of the long, ATP-inhibited K(IR)6.0 pores of K-ATP channels are ABC proteins, SURs, receptors for channel opening and closing drugs. Several competing models for SUR/K-IR coupling exist. We show that SUR TMD0, the N-terminal bundle of five transmembrane helices, specifically associates with K(IR)6.2, forcing nearly silent pores to burst like native KATP channels and enhancing surface expression. Inclusion of adjacent submembrane residues of L0, the linker between TMD0 and the stimulatory nucleotide- and drug-binding ABC core, generates constitutively active channels, whereas additional cytoplasmic residues counterbalance this activation establishing a relationship between the mean open and burst times of intact pores. SUR fragments, lacking TMD0, fail to modulate K-IR. TMD0 is thus the domain that anchors SUR to the K-IR pore. Consistent with data on chimeric ABCC/K(IR)s and a modeled channel structure, we propose that interactions of TMD0-L0 with the outer helix and N terminus of K-IR bidirectionally modulate gating. The results explain and predict pathologies associated with alteration of the 5' ends of clustered ABCC8 (9)/KCNJ11 (8) genes.