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Structural basis for the nuclear import of the human androgen receptor

Cutress, Mark L., Whitaker, Hayley C., Mills, Ian G., Stewart, Murray, Neal, David E.·2008·Journal of Cell Science
DOI 10.1242/jcs.022103
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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 5α-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-α, 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-α directly, albeit more weakly than the NLS of SV40 or nucleoplasmin. We describe the 2.6-Å-resolution crystal structure of the importin-α–AR-NLS complex, and show that the AR binds to the major NLS-binding site on importin-α 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-α 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.

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Metadata

Authors
Cutress, M. L., Whitaker, H. C., Mills, I. G., Stewart, M., & Neal, D. E.
Venue
Journal of Cell Science
Publisher
The Company of Biologists
Published
2008-04-01
Volume
121
Issue
7
Pages
957-968
ISSN
  • 0021-9533 (ISSN-L)
  • 1477-9137
DOI
10.1242/jcs.022103
OpenAlex
W2132172347
Cited by
223
References
8
FWCI
5.58
Type
journal article
Language
en
Open access
closed

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Cutress, M. L., Whitaker, H. C., Mills, I. G., Stewart, M., & Neal, D. E. (2008). Structural basis for the nuclear import of the human androgen receptor. Journal of Cell Science. https://doi.org/10.1242/jcs.022103

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