Effect of Calcium Ion on Synaptotagmin-like Protein During Pre-fusion of Vesicle for Exocytosis in Blood-brain Barrier

Background: Calcium signaling and membrane fusion play key roles in exocytosis of drug-containing vesicles through the blood-brain barrier (BBB). Identifying the role of synaptotagmin-like protein4-a (Slp4-a) in the presence of Ca ions, at the pre-fusion stage of a vesicle with the basolateral membrane of endothelial cell, can reveal brain drug transportation across BBB.

Methods: We utilized molecular dynamics (MD) simulations with a coarse-grained PACE force field to investigate the behaviors of Slp4-a with vesicular and endothelial membranes at the pre-fusion stage of exocytosis since all-atom MD simulation or experiments are more time-consuming and expensive to capture these behaviors.

Results: The Slp4-a pulls lipid membranes (vesicular and endothelial) into close proximity and disorganizes lipid arrangement at contact points, which are predictors for initiation of fusion. Our MD results also indicate that Slp4-a needs Ca to bind with weakly-charged POPE lipids (phosphatidylethanolamine).

Conclusions: Slp4-a is an important trigger for membrane fusion in BBB exocytosis. It binds to lipid membranes at multiple binding sites and triggers membrane disruption for fusion in calcium-dependent case.

General Significance: Understanding the prefusion process of the vesicle will help to design better drug delivery mechanisms to the brain through formidable BBB.