Opening Pandora‘s Jar: A Primer on the Putative Roles of Crmp2 In A Panoply of Neurodegenerative, Sensory and Motor Neuron, and Central Disorders

Abstract

CRMP2, also known as DPYSL2/DRP2, Unc-33, Ulip or TUC2, is a cytosolic phosphoprotein that mediates axon/dendrite specification and axonal growth. Mapping the CRMP2 interactome has revealed previously unappreciated functions subserved by this protein. Together with its canonical roles in neurite growth and retraction and kinesin-dependent axonal transport, it is now known that CRMP2 interacts with numerous binding partners to affect microtubule dynamics; protein endocytosis and vesicular cycling, synaptic assembly, calcium channel regulation and neurotransmitter release. CRMP2 signaling is regulated by post-translational modifications, including glycosylation, oxidation, proteolysis and phosphorylation; the latter being a fulcrum of CRMP2 functions. Here, the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders are discussed and evidence is presented for therapeutic strategies targeting CRMP2 functions.

A single structurally conserved SUMOylation site in CRMP2 controls NaV1.7 function

“…5B), confirming that the conserved residues R496 and E221 form a salt bridge as previously observed for other CRMPs. 29,37,38 The CRMP2 sequence extends another 76 residues beyond this point and contains multiple phosphorylation sites (see review 25 ) but has been predicted to be disordered. 34 We speculate that the role of this conserved salt bridge is to anchor and position the C-terminus and it's multiple regulation sites at the surface of the protein to facilitate recognition and modification.…”

“…22,23 An interaction between calcium channels and CRMP2 is regulated by Cdk5 phosphorylation. 24 Indeed, CRMP2 functions are determined by an interplay of multiple posttranslational modifications including glycosylation, oxidation, proteolysis, phosphorylation, and SUMOylation (for review see 25 ). Most recently, we identified SUMOylation as a posttranslational modification that targets CRMP2.…”

Mapping CRMP3 domains involved in dendrite morphogenesis and voltage-gated calcium channel regulation

“…CRMPs constitute a family of proteins expressed abundantly in the nervous system (Wang and Strittmatter, 1996;Quach et al, 1997;Quach et al, 2000) involved in the control of growth/ collapse of neurites (Charrier et al, 2003;Schmidt and Strittmatter, 2007), synaptic activity Wang et al, 2010;Khanna et al, 2012) and nociceptor excitability (Piekarz et al, 2012). Five isoforms of CRMPs have been identified in mammals.…”

SUMOylation alters CRMP2 regulation of calcium influx in sensory neurons

“…1 Recent mapping of the CRMP2 interactome has, with great alacrity, revealed novel functions including regulation of microtubule dynamics, protein endocytosis and vesicle recycling, as well as synaptic assembly (reviewed in ref. 2). While extensive post-translational modifications of CRMP2, including glycosylation, oxidation, proteolysis, and phosphorylation have been reported, it is unclear as to exactly how these post-translational modifications affect CRMP2's interactions and functional regulation of its burgeoning proteome.…”

“…3 Facile phosphorylation of CRMP2 increased its association with CaV2.2 6 further supporting the importance of a "tunable" interaction, especially in light of findings that disruption of the CRMP2/CaV2. 2 …”