Abstract
Protein recruitment to specific membrane locations may be governed or facilitated by electrostatic attraction, which originates from a multivalent ligand. Here we explored the energetics of a model system in which this simple electrostatic recruitment mechanism failed. That is, basic poly-L-lysine binding to one leaflet of a planar lipid bilayer did not recruit the triply-charged peptide (O-Pyromellitylgramicidin). Clustering was only observed in cases where PLL was bound to both channel ends. Clustering was indicated (i) by the decreased diffusional PLL mobility DPLL and (ii) by an increased lifetime τPLL of the clustered channels. In contrast, if PLL was bound to only one leaflet, neither DPLL nor τP changed. Simple calculations suggest that electrostatic repulsion of the unbound ends prevented neighboring OPg dimers from approaching each other. We believe that a similar mechanism may also operate in cell signaling and that it may e.g. contribute to the controversial results obtained for the ligand driven dimerization of G protein-coupled receptors.
Highlights
The association of proteins with the surfaces of plasma membranes or intracellular membranes is tightly regulated
Membrane affinity may be solely provided by electrostatic attraction of amino acid residues, which concentrate in the tertiary structure to form a binding surface [1]
Planar membranes Vertical planar bilayer lipid membranes were formed by painting diphytanoyl phosphatidylcholine (DPhPC) solution in decane (20 mg/ml) over an aperture (500 mm in diameter) in a diaphragm separating two aqueous solutions
Summary
The association of proteins with the surfaces of plasma membranes or intracellular membranes is tightly regulated. Membrane affinity may be solely provided by electrostatic attraction of amino acid residues, which concentrate in the tertiary structure to form a binding surface [1]. Phospholipid binding domains may be engaged, including e.g. pleckstrin homology domains and Fab domains [2]. When these domains interact with membranes, it involves stereospecific recognition of membrane targets like diacylglycerol and phosphoinositides. Protein attraction to the membrane may be aided by electrostatic or hydrophobic protein-lipid or proteinprotein interactions. Simultaneous involvement of several detection mechanisms is believed to be responsible for the restricted, rather than uniform distribution of recruited proteins across intracellular membranes. While the benefit of cluster formation for signaling purposes is immediately evident, the affinity requirements for protein and lipid recruitment into these clusters are less clear [2]
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