Transmembrane Structural Linkage Mechanism of the Full-Length CD44 Regulated by Palmitoylation and Hyaluronan in a Phase-segregated Membrane Environment
Description
Cluster of Differentiation 44 (CD44), as a single-pass transmembrane glycoprotein, is closely implicated with cellular adhesion and migration mediated by intracellular palmitoylations and ligand-binding to extracellular matrix components like hyaluronan (HA). However, a lack of full-length structural information and experiment-unpredicted transformation dynamics make the transmembrane structural linkage mechanism remain elusive. In this study, we validated the full-length structure of CD44 protein predicted by RosettaFold combined with all-atom molecular dynamic simulation, and then conducted extensive coarse-grained molecular dynamic simulations to investigate its translocation and transformation details modulated by different palmitoylations and HAs varied with molecular weights in a “lipid raft” including membrane. It is found that the transmembrane domain inclines to obliquely insert lipid raft by the intracellular domain (CTD) where more palmitoylated modifications occur. The raft-attachment of the CTD results in a membrane-bury of the FERM-binding domain while a release of the Ankyrin-binding domain, a cytoskeleton selection relevance of CD44. Moreover, palmitoylations on the CTD is found to change the extracellular hyaluronan-binding domain (HABD) from a lipid raft back state of CD44 to face toward lipid raft, demonstrating the inside-out structural linkage. Introduction of HAs, especially the HA in a longer chain, further stabilizes the HABD-raft attachment state. Note that the HA-binding is helpful for exposure of the CTD AnkyrinBD, revealing out an outside-in signaling transduction. The elaborated transmembrane structural linking mechanism of CD44 regulated by palmitoylation and ligand biding can provide substantial understanding for protein bidirectional transmembrane signal transduction and future targeted intervention study.
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Institutions
- Hebei University of TechnologyTianjin, Tianjin