Molecular basis for specificity of nuclear import and prediction of nuclear localization

Biochim Biophys Acta. 2011 Sep;1813(9):1562-77. doi: 10.1016/j.bbamcr.2010.10.013. Epub 2010 Oct 25.


Although proteins are translated on cytoplasmic ribosomes, many of these proteins play essential roles in the nucleus, mediating key cellular processes including but not limited to DNA replication and repair as well as transcription and RNA processing. Thus, understanding how these critical nuclear proteins are accurately targeted to the nucleus is of paramount importance in biology. Interaction and structural studies in the recent years have jointly revealed some general rules on the specificity determinants of the recognition of nuclear targeting signals by their specific receptors, at least for two nuclear import pathways: (i) the classical pathway, which involves the classical nuclear localization sequences (cNLSs) and the receptors importin-α/karyopherin-α and importin-β/karyopherin-β1; and (ii) the karyopherin-β2 pathway, which employs the proline-tyrosine (PY)-NLSs and the receptor transportin-1/karyopherin-β2. The understanding of specificity rules allows the prediction of protein nuclear localization. We review the current understanding of the molecular determinants of the specificity of nuclear import, focusing on the importin-α•cargo recognition, as well as the currently available databases and predictive tools relevant to nuclear localization. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Active Transport, Cell Nucleus / physiology*
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Databases, Protein
  • Humans
  • Mice
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Localization Signals / chemistry
  • Nuclear Localization Signals / genetics
  • Nuclear Localization Signals / physiology*
  • Parathyroid Hormone-Related Protein / chemistry
  • Parathyroid Hormone-Related Protein / physiology
  • Protein Interaction Domains and Motifs
  • Signal Transduction / physiology
  • Sterol Regulatory Element Binding Protein 2 / chemistry
  • Sterol Regulatory Element Binding Protein 2 / physiology
  • alpha Karyopherins / chemistry
  • alpha Karyopherins / physiology
  • beta Karyopherins / chemistry
  • beta Karyopherins / physiology


  • Nuclear Localization Signals
  • Parathyroid Hormone-Related Protein
  • Sterol Regulatory Element Binding Protein 2
  • alpha Karyopherins
  • beta Karyopherins