Many cellular processes rely on the recognition of cell membranes by peripheral membrane-binding proteins to effect downstream processes such as immune activation or phagocytosis. The lipid composition of these target cell membranes acts as the signal for many of these proteins. However, it is difficult to quantify the sensitivity of these proteins for the lipid composition without a full understanding of the molecular mechanisms underlying their sensitivity. Using x-ray reflectivity on lipid monolayers and molecular dynamics simulations of lipid bilayers, we examined the bound state of the murine members of the Transmembrane Immunoglobulin and Mucin (TIM) domain-containing protein family in order to identify the molecular mechanisms they leverage to associate with phosphatidylserine (PS) containing membranes. Our results suggest the TIM proteins utilize a complex combination of calcium coordination, charge and hydrophobic interactions in order to recognize membrane PS. From these results, we developed a mathematical model for equilibrium binding that incorporated these modes of interactions in order to describe the dependence on lipid composition. Furthermore, this mathematical model provides a general paradigm for determining the correct binding equation for many other peripheral membrane-binding proteins.

Lipid composition dependence of peripheral membrane-binding proteins as revealed by their membrane-bound structures

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