(469d) Effect of Post-Translational Modification on the Self-Assembly of Membrane Proteins

Palmitoylation has been shown to play role in several regulatory functions within the cell including protein sorting, trafficking and protein-protein interactions. However, the exact mechanism of the events leading to the regulatory outcome is still unclear. In this study, we investigated the effects of addition of palmitoyl chains to claudin-5 protein, a vital component of the blood-brain barrier tight junctions, using molecular dynamics simulations. We studied separate systems with single and multiple claudin proteins, each embedded in membranes with varying compositions to mimic different environments encountered along the secretory pathway – endoplasmic reticulum, Golgi complex, and the plasma membrane. We found that palmitoylation caused claudins to localize in the higher-ordered membrane domains, especially in the cholesterol-rich membranes, and restricted key claudin protein-protein conformations due to steric hindrance favoring conformations that allow pore formation in the tight junctions. The results indicate that the interplay of palmitoylated claudin proteins and lipid membrane composition influence the tight junction assembly, which in turn show a promising effect on permeability of the BBB tight junctions.