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

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 membr...