Phosphatidylglyerol Lipid Binding at the Active Site of an Intramembrane Protease.

Transmembrane substrate cleavage by the small Escherichia coli rhomboid protease GlpG informs on mechanisms by which lipid interactions shape reaction coordinates of membrane-embedded enzymes. Here, I review and discuss new work on the molecular picture of protein-lipid interactions that might govern the formation of the substrate-enzyme complex in fluid lipid membranes. Negatively charged PG-type lipids are of particular interest, because they are a major component of bacterial membranes. Atomistic computer simulations indicate POPG and DOPG lipids bridge remote parts of GlpG and might pre-occupy the substrate-docking site. Inhibition of catalytic activity by PG lipids could arise from ligand-like lipid binding at the active site, which could delay or prevent substrate docking. Dynamic protein-lipid H-bond networks, water access to the active site, and fluctuations in the orientation of GlpG suggest that GlpG has lipid-coupled dynamics that could shape the energy landscape of transmembrane substrate docking.