Amino acid sequence conservation of the algesic fragment of myelin basic protein is required for its interaction with CDK5 and function in pain

Neurotrauma frequently results in neuropathic pain. Our earlier studies revealed that peripheral neurotrauma-induced fragmentation of the myelin basic protein (MBP), a major component of the myelin sheath formed by Schwann cells, initiates a pain response from light touch stimuli (mechanical allodynia) in rodents. Here, we identified the cyclin-dependent kinase 5 (CDK5), as an intracellular interactor of MBP in Schwann cells. The algesic peptide fragment of MBP directly associated with CDK5. When complexed with its p25 coactivator, CDK5 phosphorylated the conserved MBP sequence. The expressed MBP fragment colocalized with CDK5 in Schwann cell protrusions. Roscovitine, an ATP-competitive CDK5 inhibitor, disrupted localization of the expressed MBP peptide. Mutations in the evolutionary conserved MBP algesic sequence resulted in the interference with intracellular trafficking of the MBP fragment and kinase activity of CDK5 and diminished pain-like behavior in rodents. Our findings show that MBP fragment amino acid sequence conservation determines its interactions, trafficking, and pronociceptive activity. Because CDK5 activity controls both neurogenesis and nociception, the algesic MBP fragment may be involved in the regulation of the CDK5 functionality in pain signaling and postinjury neurogenesis in vertebrates. DatabaseThe novel RNA-seq datasets were deposited in the GEO database under the accession number .