Type 1B: Myelin protein zero/P0 phosphorylation and function require an adaptor

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J Cell Biol. 2007 May 14

Myelin protein zero/P0 phosphorylation and function require an

adaptor protein linking it to RACK1 and PKC{alpha}

Gaboreanu AM, Hrstka R, Xu W, Shy M, Kamholz J, Lilien J, Balsamo J.

Department of Biological Sciences, The University of Iowa, Iowa

City, IA 52242.

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 Calpha (PKCalpha) substrate motif

(198HRSTK201) or alter serines 199 and/or 204 eliminate P0-mediated

adhesion.

Mutation in the PKCalpha substrate motif (R198S) also causes a form

of inherited peripheral neuropathy (Charcot Marie Tooth disease

[CMT] 1B), indicating that PKCalpha-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.