Paper Info
Title
Molecular mechanism for bidirectional regulation of CD44 for lipid raft affiliation by palmitoylations and PIP2.
Abstract
The co-localization of Cluster-of-Differentiation-44 protein (CD44) and cytoplasmic adaptors in specific membrane environments is crucial for cell adhesion and migration. The process is controlled by two different pathways: On the one hand palmitoylation keeps CD44 in lipid raft domains and disables the linking to the cytoplasmic adaptor, whereas on the other hand, the presence of phosphatidylinositol-4,5-biphosphate (PIP2) lipids accelerates the formation of the CD44-adaptor complex. The molecular mechanism explaining how CD44 is migrating into and out of the lipid raft domains and its dependence on both palmitoylations and the presence of PIP2 remains, however, elusive. In this study, we performed extensive molecular dynamics simulations to study the raft affinity and translocation of CD44 in phase separated model membranes as well as more realistic plasma membrane environments. We observe a delicate balance between the influence of the palmitoylations and the presence of PIP2 lipids: whereas the palmitoylations of CD44 increases the affinity for raft domains, PIP2 lipids have the opposite effect. Additionally, we studied the association between CD44 and the membrane adaptor FERM in dependence of these factors. We find that the presence of PIP2 lipids allows CD44 and FERM to associate in an experimentally observed binding mode whereas the highly palmitoylated species shows no binding affinity. Together, our results shed light on the sophisticated mechanism on how membrane translocation and peripheral protein association can be controlled by both protein modifications and membrane composition. Author summary Cytoskeleton protein complex involving with association of CD44 and ERMs is critical for cancer-related cellular adhesion and migration. The protein interactions are found to be modulated by chemical modification and membrane microenvironments, but the inherent mechanism is unclear. We obtained molecular dynamic details of CD44 localization switching between raft/non-raft subdomains regulated by palmitoylations and PIP2 molecules. Binding of PIP2 on the palmitoylated CD44 enables it to release from lipid raft, revealing an exceptional role of PIP2 in mediating protein translocation. PIP2 is beneficial for CD44 to associate with the active domain of ERM, in a nearly crystal structure mode. The molecular information will enhance our understanding for PIP2 regulation to protein translocation and membrane association.
Year
DOI
Venue
2020
10.1371/journal.pcbi.1007777
PLOS COMPUTATIONAL BIOLOGY
DocType
Volume
Issue
Journal
16
4
ISSN
Citations 
PageRank 
1553-734X
0
0.34
References 
Authors
0
6
Name
Order
Citations
PageRank
Fude Sun100.34
Carsten F E Schroer200.34
Carlos R Palacios300.34
Lida Xu400.34
Shi-Zhong Luo501.01
Siewert J. Marrink620.72