Exploring the C‐Terminal Tail Dynamics: Structural and Molecular Perspectives into the Therapeutic Activities of Novel CRMP‐2 Inhibitors, Naringenin and Naringenin‐7‐O‐glucuronide, in the Treatment of Alzheimer's Disease

Abstract

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 remains 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 structural insights provide mechanistic events that could contribute towards the structure‐based design of anti‐AD molecules which can bind CRMP2 selectively and alter its phosphorylation process.

On the Neuroprotective Effects of Naringenin: Pharmacological Targets, Signaling Pathways, Molecular Mechanisms, and Clinical Perspective

“…Before the binding of naringenin and naringenin-7- O -glucuronide to the C-terminal tail, these residues have more flexibility, activity, and are more susceptible to phosphorylation. But these effects reversed after binding of naringenin and naringenin-7- O -glucuronide [59]. On this regard, another molecular docking study demonstrated that the occupation of CRMP2 by naringenin restricts the access of the phosphorylated enzyme to the terminal H19 helix especially in Tyr479 residue which is the susceptible residue for phosphorylation [60].…”

Crmp4-KO Mice as an Animal Model for Investigating Certain Phenotypes of Autism Spectrum Disorders

“…Genome-wide studies, genetic linkage analyses, proteomic analyses, and translational approaches have revealed altered expression levels of CRMPs in neurodevelopmental disorders, such as schizophrenia, attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) [3,4,5,6,7,8]. Similar findings have been observed for neurological disorders such as Alzheimer’s disease [9,10,11] and hyperalgesia syndrome [12,13,14,15]. Furthermore, during the past decade, many studies using knockout (KO) mice have demonstrated the role of CRMPs in the pathogenesis of neurodevelopmental disorders, as described in Section 3 below.…”

Collapsin Response Mediator Proteins: Their Biological Functions and Pathophysiology in Neuronal Development and Regeneration

“…Several small molecules that have been shown to bind CRMP2 are lacosamide (Wilson et al, 2012(Wilson et al, , 2014, lanthionine ketimine (LK; Hensley et al, 2010aHensley et al, , 2013Hensley and Harris-White, 2015), edonerpic maleate (Abe et al, 2018) and naringenin (Ghofrani et al, 2015;Lawal et al, 2018). These molecules are considered candidates for application in the treatment of some of the CRMP2-related pathological conditions discussed above.…”

“…Naringenin has demonstrated the ability to bind and decrease CRMP2 phosphorylation (Yang et al, 2016;Lawal et al, 2018). This action of changing CRMP2's phosphorylated status and hence the binding of cytoskeletal elements may account for the ability of naringenin to improve AD pathology and cognitive deficits in mouse models of AD.…”