8ti2

From Proteopedia

Cryo-EM structure of a SUR1/Kir6.2-Q52R ATP-sensitive potassium channel in the presence of PIP2 in the open conformation

Structural highlights

8ti2 is a 8 chain structure with sequence from Mesocricetus auratus and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.28Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KCJ11_RAT This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium. Can form cardiac and smooth muscle-type KATP channels with ABCC9. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation (By similarity).

Publication Abstract from PubMed

ATP-sensitive potassium (K(ATP)) channels, composed of four pore-lining Kir6.2 subunits and four regulatory sulfonylurea receptor 1 (SUR1) subunits, control insulin secretion in pancreatic beta-cells. K(ATP) channel opening is stimulated by PIP(2) and inhibited by ATP. Mutations that increase channel opening by PIP(2) reduce ATP inhibition and cause neonatal diabetes. Although considerable evidence has implicated a role for PIP(2) in K(ATP) channel function, previously solved open-channel structures have lacked bound PIP(2), and mechanisms by which PIP(2) regulates K(ATP) channels remain unresolved. Here, we report the cryoEM structure of a K(ATP) channel harboring the neonatal diabetes mutation Kir6.2-Q52R, in the open conformation, bound to amphipathic molecules consistent with natural C18:0/C20:4 long-chain PI(4,5)P(2) at two adjacent binding sites between SUR1 and Kir6.2. The canonical PIP(2) binding site is conserved among PIP(2)-gated Kir channels. The non-canonical PIP(2) binding site forms at the interface of Kir6.2 and SUR1. Functional studies demonstrate both binding sites determine channel activity. Kir6.2 pore opening is associated with a twist of the Kir6.2 cytoplasmic domain and a rotation of the N-terminal transmembrane domain of SUR1, which widens the inhibitory ATP binding pocket to disfavor ATP binding. The open conformation is particularly stabilized by the Kir6.2-Q52R residue through cation-pi bonding with SUR1-W51. Together, these results uncover the cooperation between SUR1 and Kir6.2 in PIP(2) binding and gating, explain the antagonistic regulation of K(ATP) channels by PIP(2) and ATP, and provide a putative mechanism by which Kir6.2-Q52R stabilizes an open channel to cause neonatal diabetes.

Structure of an open K(ATP) channel reveals tandem PIP(2) binding sites mediating the Kir6.2 and SUR1 regulatory interface.,Driggers CM, Kuo YY, Zhu P, ElSheikh A, Shyng SL Nat Commun. 2024 Mar 20;15(1):2502. doi: 10.1038/s41467-024-46751-5. PMID:38509107^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Driggers CM, Kuo YY, Zhu P, ElSheikh A, Shyng SL. Structure of an open K(ATP) channel reveals tandem PIP(2) binding sites mediating the Kir6.2 and SUR1 regulatory interface. Nat Commun. 2024 Mar 20;15(1):2502. PMID:38509107 doi:10.1038/s41467-024-46751-5