Mechanism of Lipid Modulation in Ion Channels
Membrane proteins are continuously exposed to the complex lipid environment of cellular membranes, yet how specific lipids regulate their function remains poorly understood. In this talk, I will discuss two examples illustrating how membrane lipids tune ion-channel activity through defined structural mechanisms. First, I will describe how lipids regulate temperature sensitivity in SthK, a
bacterial ion channel that is activated by cold temperatures. We find that a functionally important, state-dependent intersubunit salt bridge acts as a temperature sensor, while lipid binding tunes temperature sensitivity by modulating the strength of this interaction. These findings suggest a general mechanism by which thermosensitivity can emerge from the interplay between protein energetics and the membrane environment. Second, I will discuss regulation of rod photoreceptor cyclic nucleotide-gated (CNG) channels by the signaling lipid PI(4,5)P2 (PIP2). Although PIP2 was known to inhibit CNG channels, its very low abundance in rod outer segments raised questions about the physiological relevance of this effect. We show that
PIP2 potently inhibits CNG channels at physiologically relevant concentrations (<0.2 mol%) and identify its binding site and mechanism of action. PIP2 binds to an allosteric site that stabilizes the closed channel and impedes conformational changes required for opening. Identification of this regulatory site also reveals a potential target for pharmacological modulation of CNG channels.
Together, these studies demonstrate how specific lipid–protein interactions can reshape the energetic landscape of ion channels to control physiologically important aspects of their function.
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For any questions, please contact Hyacinth Camillieri at hcamillieri@gc.cuny.edu