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Palmitoylation of Claudin‑5 Proteins Influences Their Lipid Domain Affinity and Tight Junction Assembly at the Blood–Brain Barrier Interface

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posted on 2019-01-10, 00:00 authored by Nandhini Rajagopal, Flaviyan Jerome Irudayanathan, Shikha Nangia
Post-translational lipid modification of integral membrane proteins is recognized as a key mechanism to modulate protein–protein and membrane–protein associations. Despite numerous reports of lipid-modified proteins, molecular-level understanding of the influence of lipid-modification of key membrane proteins remains elusive. This study focuses on the lipid modification of one such proteinclaudin-5, a critical component of the blood–brain barrier tight junctions. Claudin-5 proteins are responsible for regulating the size and charge-selective permeability at the blood–brain interface. Palmitoylation of the claudin family of proteins is implicated in influencing the tight junction permeability in prior experimental studies. Here, we investigate the impact of palmitoylation on claudin-5 self-assembly using multiscale molecular simulations. To elucidate protein–membrane interactions, we used three model membrane compositions (endoplasmic reticulum, cholesterol-enriched endoplasmic reticulum, and plasma membrane) that mimic the complexity of cell organelles encountered by a typical membrane protein in its secretion pathway. The results show that palmitoylation enhances protein’s affinity for cholesterol-rich domains in a membrane, and it can elicit a site-specific response based on the location of the palmitoyl chain on the protein. Also, in claudin-5 self-assembly, palmitoylation restricts specific protein–protein conformations. Overall, this study demonstrates the significance of post-translational lipid modification of proteins in cellular and subcellular membranes, and the impact palmitoylation can have on critical cellular functions of the protein.

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