Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2
By S. Hansen, X. Tao, R. MacKinnon. Nature, 2011
603 citations recorded by the source corpus.
The regulation of ion channel activity by specific lipid molecules is widely recognized as an integral component of electrical signalling in cells. In particular, phosphatidylinositol 4,5-bisphosphate (PIP2), a minor yet dynamic phospholipid component of cell membranes, is known to regulate many different ion channels. PIP2 is the primary agonist for classical inward rectifier (Kir2) channels, through which this lipid can regulate a cell’s resting membrane potential. However, the molecular mechanism by which PIP2 exerts its action is unknown. Here we present the X-ray crystal structure of a Kir2.2 channel in complex with a short-chain (dioctanoyl) derivative of PIP2. We found that PIP2 binds at an interface between the transmembrane domain (TMD) and the cytoplasmic domain (CTD). The PIP2-binding site consists of a conserved non-specific phospholipid-binding region in the TMD and a specific phosphatidylinositol-binding region in the CTD. On PIP2 binding, a flexible expansion linker contracts to a compact helical structure, the CTD translates 6 Å and becomes tethered to the TMD and the inner helix gate begins to open. In contrast, the small anionic lipid dioctanoyl glycerol pyrophosphatidic acid (PPA) also binds to the non-specific TMD region, but not to the specific phosphatidylinositol region, and thus fails to engage the CTD or open the channel. Our results show how PIP2 can control the resting membrane potential through a specific ion-channel-receptor–ligand interaction that brings about a large conformational change, analogous to neurotransmitter activation of ion channels at synapses.
Subfields: Cellular and Molecular Neuroscience, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/04750143a88d16a965f2f5a2e392dc4d783cb3b1
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Citations in the corpus
- Phosphoinositides: tiny lipids with giant impact on cell regulation. (2013, background): “2 K channel, PtdIns(4,5)P2 binds at an interface between the transmembrane domain (TMD) and the cytoplasmic domain of the channel such that the fatty acid chains interact with the TMD and the phosphorylated headgroup with the cytoplasmic domain bringing the latter closer to the membrane and helping ”
- hERG K(+) channels: structure, function, and clinical significance. (2012, background): “Subsequently, these models of the pore have been validated by crystal structures of multiple K channel proteins (111, 150, 244, 297, 337, 384, 386, 619, 682), as well as a bacterial voltage-gated Na channel (479).”
- TRP channels and pain. (2013, background): “…leaflet of the plasma membrane (Chuang et al. 2001, Prescott & Julius 2003, Ufret-Vincenty et al. 2011), reminiscent of well-studied interactions between PIP2 and cytoplasm-facing residues of inwardly rectifying potassium channels (Gamper & Rohacs 2012, Hansen et al. 2011, Hilgemann et al. 2001).”