Structural basis for the nuclear import of the human androgen receptor

Mark L Cutress, Hayley C Whitaker, Ian G Mills, Murray Stewart, David E Neal

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

Ligand-dependent nuclear import is crucial for the function of the androgen receptor (AR) in both health and disease. The unliganded AR is retained in the cytoplasm but, on binding 5alpha-dihydrotestosterone, it translocates into the nucleus and alters transcription of its target genes. Nuclear import of AR is mediated by the nuclear import factor importin-alpha, which functions as a receptor that recognises and binds to specific nuclear localisation signal (NLS) motifs on cargo proteins. We show here that the AR binds to importin-alpha directly, albeit more weakly than the NLS of SV40 or nucleoplasmin. We describe the 2.6-angstroms-resolution crystal structure of the importin-alpha-AR-NLS complex, and show that the AR binds to the major NLS-binding site on importin-alpha in a manner different from most other NLSs. Finally, we have shown that pathological mutations within the NLS of AR that are associated with prostate cancer and androgen-insensitivity syndrome reduce the binding affinity to importin-alpha and, subsequently, retard nuclear import; surprisingly, however, the transcriptional activity of these mutants varies widely. Thus, in addition to its function in the nuclear import of AR, the NLS in the hinge region of AR has a separate, quite distinct role on transactivation, which becomes apparent once nuclear import has been achieved.

Original languageEnglish
Pages (from-to)957-68
Number of pages12
JournalJournal of Cell Science
Volume121
Issue numberPt 7
DOIs
Publication statusPublished - 01 Apr 2008

Keywords

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Blotting, Western
  • COS Cells
  • Cell Nucleus
  • Cercopithecus aethiops
  • Crystallography, X-Ray
  • Humans
  • Models, Biological
  • Molecular Sequence Data
  • Nuclear Localization Signals
  • Protein Binding
  • Protein Structure, Secondary
  • Receptors, Androgen
  • Sequence Homology, Amino Acid
  • alpha Karyopherins

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