Structural basis of PIP2 activation of the classicalinward rectifier K+ channel Kir2.2

摘要

The regulation of ion channel activity by specific lipid molecules is widely recognized as an integral component of electrical signalling in cells'-2. In particular, phosphatidylinositol 4,5-bisphosphate (PIP_2), a minor yet dynamic phospholipid component of cell membranes, is known to regulate many different ion channels2"8. PIP_2 is the primary agonist for classical inward rectifier (Kir2) channels, through which this lipid can regulate a cell's resting membrane potential~(2'79). However, the molecular mechanism by which PIP_2 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 PIP_2. We found that PIP_2 binds at an interface between the trans-membrane domain (TMD) and the cytoplasmic domain (CTD). The PIP_2-binding site consists of a conserved non-specific phospholipid-binding region in the TMD and a specific phosphatidylinositol-binding region in the CTD. On PIP_2 binding, a flexible expansion linker contracts to a compact helical structure, the CTD translates 6 A and becomes tethered to the TMD and the inner helix gate begins to open. In contrast, the small anionic lipid dioctanoyl