Karyopherin-β2 Recognition of a PY-NLS Variant that Lacks the Proline-Tyrosine Motif

Karyopherin-β2 or Transportin-1 binds proline-tyrosine nuclear localization signals (PY-NLSs) in its cargos. PY-NLSs are described by structural disorder, overall positive charge, and binding epitopes composed of an N-terminal hydrophobic or basic motif and a C-terminal R-X_2-5P-Y motif. The N-terminal tail of histone H3 binds Kapβ2 with high affinity but does not contain a recognizable PY-NLS. The crystal structure of the Kapβ2-H3 tail shows residues 11-27 of H3 binding to the PY-NLS site of Kapβ2. H3 residues ¹¹TGGKAPRK¹⁸ bind the site for PY-NLS Epitope 1 (N-terminal hydrophobic/basic motif), which is most important for Kapβ2-binding. H3 residue Arg26 occupies the PY-NLS Epitope 2 position (usually arginine of R-X_2-5P-Y) but PY-NLS Epitope 3 (proline-tyrosine motif) is missing in the H3 tail. Histone H3 thus provides an example of a PY-NLS variant with no proline-tyrosine or homologous proline-hydrophobic motif. The H3 tail uses a very strong Epitope 1 to compensate for loss of the often-conserved proline-tyrosine epitope.