(770e) Role of Posttranslational Modifications on Protein-Lipid Interactions

Palmitoylation, a post-translational lipid modification, has been suggested to regulate protein partitioning into membrane nanodomains or rafts. Owing to the dynamic and reversible nature, the role of palmitoylation is considered crucial in the study of neurodegenerative diseases, cancer, and diabetes. In our recent work, we used atomistic and coarse-grained molecular dynamics simulations to study preferential partitioning behavior of proteins upon palmitoylation.¹ Based on the insights gained from our results, we hypothesized that location of the palmitoyl chain in the protein’s secondary structure (cytosolic loop versus transmembrane) has a significant role in influencing the protein partitioning into membrane rafts. To test the hypothesis, we used high-performance Anton2 computer to study three transmembrane proteins with varying locations of cytosolic and transmembrane palmitoyl sites. The results confirm our hypothesis and clearly demonstrate that palmitoyl chains in the cytosolic loop region have opposite behavior compared to their counterparts in transmembrane location. This work indicates that subtle changes in palmitoylation have an enormous impact on the protein-lipid interactions. This work suggests that we are only at the inception of understanding the impact of post-translational protein modifications; much more work needs to be undertaken to appreciate its significance fully.

Reference:

1. Nandhini Rajagopal, Flaviyan Jerome Irudayanathan, and Shikha Nangia, Palmitoylation of Claudin-5 Proteins Influences Their Lipid Domain Affinity and Tight Junction Assembly at the Blood–Brain Barrier Interface, J. Phys. Chem. B, 2019, 123,983–993. DOI: 10.1021/acs.jpcb.8b09535