Effect of Palmitoylation in Membrane Proteins at the Blood-Brain Barrier Interface

Claudin family of tetraspanin transmembrane proteins form the building blocks of tight-junction barriers that regulate the diffusion of molecules through the paracellular spaces of epithelial and endothelial cells. In the lipid environment, the claudin proteins can undergo a reversible post-translational modification where long chain fatty acids covalently bond with the specific cysteine sites on the protein. Palmitoylation is implicated in the change in membrane-associated functions such as protein trafficking, cell signaling, and raft formation, among others. Studies on claudin-18 indicate that palmitoylation of claudin is essential for tight junction localization, wherein the claudins whose palmitoylation sites were mutated showed reduced localization due to poor membrane trafficking efficiency.¹ In this study, we investigate the role of palmitoylation in claudin-5 in cholesterol-rich complex membranes using coarse-grained molecular dynamics simulations. Through signature patterns in the protein sequence, four potential palmitoylation sites have been identified for claudin-5, which include the residues Cys-104, 107, 182, and 183.²Comparison of protein-lipid interactions and claudin-claudin self-assembly interaction patterns both with and without palmitoylation will be presented. The results of these molecular simulations highlight the impact of palmitoylation on protein trafficking, protein assembly, subcellular localization, and intracellular signaling.

References:

1. Van Itallie, C. M., Gambing, T. M., Carson, J. L., and Anderson, J. M., “Palmitoylation of claudins is required for efficient tight-junction localization,” Journal of Cell Science 118, pp. 1427-1436 (2005).
2. Awan, F. M., Anjum, S., Obaid, A., Ali, A., Paracha, R. Z., and Janjua, H. A., “In-silico analysis of claudin-5 reveals novel putative sites for post-translational modifications: Insights into potential molecular determinants of blood–brain barrier breach during HIV-1 infiltration,” Infection Genetics and Evolution, 27, pp. 355–365, (2014).