Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2
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- 28 August 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 477 (7365), 495-498
- https://doi.org/10.1038/nature10370
Abstract
The regulatory lipid phosphatidylinositol 4,5-bisphosphate (PIP2) is the primary activator of inward rectifier K+ (Kir) channels. Kir channels control the resting membrane potential in a wide variety of excitable cells. The X-ray crystal structure of the Kir2.2 potassium channel in complex with a PIP2 derivative has now been determined. One PIP2 molecule binds to each of the four K+ channel subunits near the membrane inner leaflet. On binding, a large conformational change occurs, causing the cytoplasmic domain to engage the transmembrane domain and the pore to open. This work shows the structural basis for the regulation of receptors and ion channels by lipids, an important factor in the control of cell signalling. The regulation of ion channel activity by specific lipid molecules is widely recognized as an integral component of electrical signalling in cells1,2. In particular, phosphatidylinositol 4,5-bisphosphate (PIP2), a minor yet dynamic phospholipid component of cell membranes, is known to regulate many different ion channels2,3,4,5,6,7,8. PIP2 is the primary agonist for classical inward rectifier (Kir2) channels, through which this lipid can regulate a cell’s resting membrane potential2,7,8,9. 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.Keywords
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