Phosphoinositide Control of Membrane Protein Function: A Frontier Led by Studies on Ion Channels

Abstract

Anionic phospholipids are critical constituents of the inner leaflet of the plasma membrane, ensuring appropriate membrane topology of transmembrane proteins. Additionally, in eukaryotes, the negatively charged phosphoinositides serve as key signals not only through their hydrolysis products but also through direct control of transmembrane protein function. Direct phosphoinositide control of the activity of ion channels and transporters has been the most convincing case of the critical importance of phospholipid-protein interactions in the functional control of membrane proteins. Furthermore, second messengers, such as [Ca2+]i, or posttranslational modifications, such as phosphorylation, can directly or allosterically fine-tune phospholipid-protein interactions and modulate activity. Recent advances in structure determination of membrane proteins have allowed investigators to obtain complexes of ion channels with phosphoinositides and to use computational and experimental approaches to probe the dynamic mechanisms by which lipid-protein interactions control active and inactive protein states.

Mutations in Nature Conferred a High Affinity Phosphatidylinositol 4,5-Bisphosphate-binding Site in Vertebrate Inwardly Rectifying Potassium Channels

“…PIP 2 is a known regulator of many ion channel and transport molecules (1,2). The solution of two crystal structures of vertebrate Kir channels complexed with PIP 2 highlights the interaction of positively charged residues between the transmembrane domain and the C terminus with the negatively charged headgroup phosphates (7,45).…”

“…Multiple positively charged residues located in the N and C termini of vertebrate Kir channels are important in coordinating with the negatively charged headgroup phosphates of PIP 2 (1,2,7,45). Do the various basic residues play equivalent roles?…”

“…This is an interesting difference, but PIP 2 is not present in the prokaryotic cell membrane (2,6), and thus its inhibitory effect on bacterial Kir channels lacks physiological relevance. Among eukaryotes, the structural basis for Kir channel activation by PIP 2 has been clarified by many studies (1,2), culminating in the co-crystallization of PIP 2 with chicken Kir2.2 (7). Among the critical components of the protein-lipid interaction are several basic residues within the channel that provide an electrostatically favorable interaction with the negative charges on the phosphate groups of PIP 2 .…”

Unifying Mechanism of Controlling Kir3 Channel Activity by G Proteins and Phosphoinositides

“…Phospholipase C (PLC) hydrolyzes PI(4,5)P 2 into inositol trisphosphate (IP 3 ) and diacylglycerol (DAG). Modified from Logothetis et al (2015).…”

Competition of calcified calmodulin N lobe and PIP2to an LQT mutation site in Kv7.1 channel

“…Phosphatidylinositol-4,5-bisphosphate (PIP 2 ) is required for proper Kv7 channel function (24,25). Earlier work mapped the site of PIP 2 binding on Kv7.2-4 channels to the long intervening linker connecting helices A and B (26).…”