Collapsin response mediator protein family
CRMPs are predominantly expressed in the nervous system during development and play important roles in axon formation from neurites and in growth cone guidance and collapse through their interactions with microtubules.
Group of researchers led by Goshima found out that CRMP-2 played a role in the transduction of the extracellular Semaphorin 3A (Sema3A), an inhibitory protein for axonal guidance in chick dorsal root ganglion (DRG).
Concurrently, a 64 kDa protein named as TOAD-64 for Turned On After Division, was shown to increase significantly during the development of the cortex of the brain.
[6] In the same year, several other studies cloned CRMPs-1-4 in rat and dihydropyrimidinase (DHPase) homologous sequence of CRMPs-1, -2, and -4 in human fetal brain.
[4] Additionally, CRMPs are homologs of Unc-33 whose mutation causes impaired ability to form neural circuits and uncoordinated mobility in Caenorhabditis elegans.
[7] CRMP1-4 genes are roughly 60% homologous with the tetramer liver dihydropyrimidinase (DHPase), and also possess a similar structure to members of the metal-dependent amidohydrolases.
However, the fact that CRMPs are not enzymatic reveals that they might lack the critical His residues that are present in amidohydrolase enzymes to allow them to bind metal atoms to their active site.
Gel filtration analysis has shown that CRMP-5 and CRMP-1 form weaker homo-tetramers compared with CRMP-2, and that divalent cations, Ca2+ and Mg2+, destabilize oligomers of CRMP-5 and CRMP-1, but promote CRMP-2 oligomerization.
[4] In the adult nervous system, CRMP expression is significantly downregulated and limited in areas associated with brain plasticity, neurogenesis, or regeneration.
Among the five members of the CRMP family, CRMP-2 is the most highly expressed in the adult brain, especially in post-mitotic neurons of the olfactory system, cerebellum, and hippocampus.
Also, injury-induced CRMPs expression is found in sprouting fibers in both the central and peripheral nervous system.
Similarly, CRMP-2 has been suggested to participate in the survival and maintenance in postmitotic neurons as its over-expression accelerates nerve regeneration.
[1] In both cases, phosphorylation of CRMP-2 at Thr-555 by Rho kinase or at Thr-509, Thr-514 or Ser-518 by GSK-3β inactivates the protein by lowering binding affinity to tubulin and Numb.
[7] In the presence of CRMP-2, the signal can induce alterations of Rac-dependent pathway, which modulates the actin filament assembly in the growth cone.
In the presence of CRMP-2, the signal can induce alterations of Rac-dependent pathway, which modulates the actin filament assembly in the growth cone.
CRMP-2 can be regulated post-translationally by O-GluNAc (β-N-acetylglucosamine linked to hydroxyls of serine or threonine) as the modification blocks CRMP-2 from being phosphorylated.
[6] Cleaved CRMP products play a considerable role in the degeneration of axons as a result of trauma inflicted on the central nervous system (CNS).
It has been shown that activated calpain proteolytically cleaves CRMP-3, creating a cleavage product of CRMP that interacts with vital cytosolic and nuclear molecules to bring about neurodegeneration.
