Karyopherin-? (Kap) proteins mediate the majority of protein transport between the nucleus and the cytoplasm. Of the 20 Kaps in human cells, 11 are import-Kaps or Importins, each recognizing a distinct set of protein cargos. This proposal describes structural, biochemical and biophysical analyses of nuclear import systems for core histones H2A/H2B and H3/H4. Here, we propose to understand how histones H2A/H2B are recognized by their primary human importer Importin-9 (Imp9) and by the homologous yeast Kap114. We will determine the mechanisms of how H2A/H2B is recognized by the Importins, how the GTPase Ran interacts with the Importin- H2A/H2B complex and how histone chaperones affect these interactions. We will also study how histones H3/H4 are recognized by their primary human importer, Importin-4 (Imp4). We will explain how histone chaperone Asf1 contributes to nuclear import of H3/H4 and how RanGTP regulates these multi-protein complexes.
Transport of histones into the nucleus is an essential and fundamental cellular process that is immediately downstream of histone synthesis/processing in the cytoplasm and immediately upstream of nucleosome assembly in the nucleus. Steps in histone processing, nuclear import and deposition are likely tightly coordinated. It is therefore important to understand the molecular mechanisms of the individual steps of histone import beyond identification of the Importins and participating histone chaperones. 1
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