Exploring the C-terminal tail dynamics: therapeutic activities of novel CRMP-2 inhibitors

What is it about?

The collapsin response mediator protein (CRMP-2) is hyperphosphorylated in Alzheimer's disease (AD). These phosphorylation events are mediated by specific kinase proteins, GSK3β and Cdk5, and occur at target phosphorylation sites majorly located at the C-terminal tail of CRMP-2. The abilities of naringenin (NAR) and naringenin-7-O-glucuronide (NAR-7-O-G) to selectively bind CRMP-2 and reduce its phosphorylation have been previously demonstrated; the molecular interplay between these events remain unresolved. Using computational tools, we unravel the possible mechanisms by which these molecules disrupt CRMP-2 phosphorylation. Structural and dynamic analyses revealed that while the C-terminal tail of unbound CRMP-2 was extended and subtly organized, notable conformational disarray and rigidity characterized this region when bound by NAR and NAR-7-O-G. Consequentially, atomistic motions of constituent phosphorylation sites were restricted, indicative of structural occurrences that could distort the accessibility of interactive kinase proteins. A similar pattern was observed at a target phosphorylation site located in the globular domain of CRMP-2. MM/PBSA analyses revealed that both compounds interacted favorably with CRMP-2 while crucial residues that enhanced their selective binding include Glu353 Thr349 Lys254 Asp140 and Arg75. These insights will enhance the structure-based design of anti-AD molecules that can selectively bind to CRMP-2 altering its phosphorylation process

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