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 proteinclaudin-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.