Myelin protein zero/P0 phosphorylation and function require an adaptor protein linking it to RACK1 and PKCα

Point mutations in the cytoplasmic domain of myelin protein zero (P0; the major myelin protein in the peripheral nervous system) that alter a protein kinase Ca (PKC alpha) substrate motif (198HRSTK201) or alter serines 199 and/ or 204 eliminate P0- mediated adhesion. Mutation in the PKCa substrate motif (R198S) also causes a form of inherited peripheral neuropathy ( Charcot Marie Tooth disease [CMT] 1B), indicating that PKC alpha-mediated phosphorylation of P0 is important for myelination. We have now identified a 65-kD adaptor protein that links P0 with the receptor for activated C kinase 1 (RACK1). The interaction of p65 with P0 maps to residues 179-197 within the cytoplasmic tail of P0. Mutations or deletions that abolish p65 binding reduce P0 phosphorylation and adhesion, which can be rescued by the substitution of serines 199 and 204 with glutamic acid. A mutation in the p65- binding sequence G184R occurs in two families with CMT, and mutation of this residue results in the loss of both p65 binding and adhesion function.