Ionic protein-lipid interactions at the plasma membrane regulate the structure and function of immunoreceptors

Abstract Adaptive lymphocytes express a panel of immunoreceptors on the cell surface. Phospholipids are the major components of cell membranes, but they have functional roles beyond forming lipid bilayers. In particular, acidic phospholipids forming microdomains in the plasma membrane can ionically interact with proteins via polybasic sequences, which can have functional consequences for the protein. We have shown that negatively charged acidic phospholipids can interact with positively charged juxtamembrane polybasic regions of immunoreceptors, such as TCR-CD3, CD28 and IgG-BCR, to regulate protein structure and function. Furthermore, we pay our attention to protein transmembrane domains. We show that a membrane-snorkeling Lys residue in integrin αLβ2 regulates transmembrane heterodimer formation and integrin adhesion through ionic interplay with acidic phospholipids and calcium ions (Ca2 +) in T cells, thus providing a new mechanism of integrin activation. Here, we review our recent progress showcasing the importance of both juxtamembrane and intramembrane ionic protein-lipid interactions.