Electrostatic switch mechanisms of membrane protein trafficking and regulation.

Lipid-protein interactions are normally classified as either specific or general. Specific interactions refer to lipid binding to specific binding sites within a membrane protein, thereby modulating the protein's thermal stability or kinetics. General interactions refer to indirect effects whereby lipids affect membrane proteins by modulating the membrane's physical properties, e.g., its fluidity, thickness, or dipole potential. It is not widely recognized that there is a third distinct type of lipid-protein interaction. Intrinsically disordered N- or C-termini of membrane proteins can interact directly but nonspecifically with the surrounding membrane. Many peripheral membrane proteins are held to the cytoplasmic surface of the plasma membrane via a cooperative combination of two forces: hydrophobic anchoring and electrostatic attraction. An acyl chain, e.g., myristoyl, added post-translationally to one of the protein's termini inserts itself into the lipid matrix and helps hold peripheral membrane proteins onto the membrane. Electrostatic attraction occurs between positively charged basic amino acid residues (lysine and arginine) on one of the protein's terminal tails and negatively charged phospholipid head groups, such as phosphatidylserine. Phosphorylation of either serine or tyrosine residues on the terminal tails via regulatory protein kinases allows for an electrostatic switch mechanism to control trafficking of the protein. Kinase action reduces the positive charge on the protein's tail, weakening the electrostatic attraction and releasing the protein from the membrane. A similar mechanism regulates many integral membrane proteins, but here only electrostatic interactions are involved, and the electrostatic switch modulates protein activity by altering the stabilities of different protein conformational states.