Phosphatidylserine Promotes Tighter Membrane Binding of Clusterin Signal Peptide over Phosphatidylglycerol, While Phosphatidylethanolamine Allows Its Deeper Penetration

The lipid specificity for proteins and peptide binding is extremely important for the biological functions of receptors and other membrane-binding proteins, and antimicrobial peptides. The signal peptide of a secretory protein guides the translocation of the nascent protein to the destination organelle, followed by its proteolytic cleavage. Clusterin, a lipid transporter, is also involved in several pathophysiological conditions such as fibrotic diseases, metabolic diseases, and cardiovascular diseases. In this present work, we have evaluated the binding affinity of the signal peptide of clusterin in membranes with different lipid compositions, with a special emphasis on evaluating the role of negatively charged lipids and an inverted cone-shaped phosphatidylethanolamine. We have further examined the effect of its binding on the membrane organization and dynamics utilizing arrays of steady-state and time-resolved fluorescence spectroscopic methods. Our results demonstrate that the signal peptide of clusterin speciates between phosphatidylglycerol and phosphatidylserine though both are negatively charged lipids. We have further shown that the phosphatidylethanolamine induces deeper penetration of the peptide in the membrane, irrespective of the presence of phosphatidylglycerol or phosphatidylserine. Taken together, our results underscore the significance of the lipidic ecosystem in mediating lipid-peptide interactions.