The 21.5-kDa isoform of myelin basic protein has a non-traditional PY-nuclear-localization signal

► Full-length 21.5-kDa MBP isoform is translocated to the nucleus. ► We hypothesized that the exon-II-encoded sequence contained the NLS. ► We mutated this sequence in RFP-tagged constructs and transfected N19-cells. ► Abolition of two key positively-charged residues resulted in loss of nuclear-trafficking. ► The 21.5-kDa isoform of classic MBP contains a non-traditional PY-NLS.