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First published online 4 March 2008
doi: 10.1242/jcs.022103

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Structural basis for the nuclear import of the human androgen receptor

¹ Uro-Oncology Research Group, Cancer Research UK Cambridge Research Institute, Robinson Way, Cambridge, CB2 0RE, UK
² MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK

^* Author for correspondence (e-mail: den22{at}medschl.cam.ac.uk)

Accepted 9 January 2008

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 5-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-, 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- directly, albeit more weakly than the NLS of SV40 or nucleoplasmin. We describe the 2.6-Å-resolution crystal structure of the importin-–AR-NLS complex, and show that the AR binds to the major NLS-binding site on importin- 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- 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.

Key words: Androgen-insensitivity syndrome, Androgen receptor, Nuclear import, Prostate cancer

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