Abstract
KATP channels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic β-cells, channels formed by SUR1 and Kir6.2 regulate insulin secretion and are the targets of antidiabetic sulfonylureas. Here, we used cryo-EM to elucidate structural basis of channel assembly and gating. The structure, determined in the presence of ATP and the sulfonylurea glibenclamide, at ~6 Å resolution reveals a closed Kir6.2 tetrameric core with four peripheral SUR1s each anchored to a Kir6.2 by its N-terminal transmembrane domain (TMD0). Intricate interactions between TMD0, the loop following TMD0, and Kir6.2 near the proposed PIP2 binding site, and where ATP density is observed, suggest SUR1 may contribute to ATP and PIP2 binding to enhance Kir6.2 sensitivity to both. The SUR1-ABC core is found in an unusual inward-facing conformation whereby the two nucleotide binding domains are misaligned along a two-fold symmetry axis, revealing a possible mechanism by which glibenclamide inhibits channel activity.
Highlights
Studies into the electric mechanisms of insulin release of the pancreatic b-cell in the early 1980s led to the discovery and identification of an ATP-sensitive potassium (KATP) channel as the key molecular link between glucose metabolism and insulin secretion (Ashcroft and Rorsman, 1990; Cook and Bryan, 1998)
Channel integrity was found to be best preserved when membranes were solubilized in digitonin and channels purified in the presence of 1 mM glibenclamide (GBC) and 1 mM ATP (Figure 1), which was the condition used for cryo-EM structure determination
The structure reported here provides the first glimpse of the detailed domain organization of KATP channels and the intricate structural interactions between SUR1 and Kir6.2
Summary
Studies into the electric mechanisms of insulin release of the pancreatic b-cell in the early 1980s led to the discovery and identification of an ATP-sensitive potassium (KATP) channel as the key molecular link between glucose metabolism and insulin secretion (Ashcroft and Rorsman, 1990; Cook and Bryan, 1998). As KATP channels set the b-cell membrane potential, this regulation by nucleotides endows them the ability to sense metabolic changes and translate those into changes in membrane excitability, which initiates or stops insulin secretion (Ashcroft, 2005). Another key player for KATP function is membrane phosphatidylinositol-4, 5-bisphosphate (PIP2); as in all other Kir family members, PIP2 is required for channel opening and sets the intrinsic open probability (Po) of the channel (Hibino et al, 2010; Nichols, 2006). KATP channels are the targets of sulfonylureas, one of the most commonly
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