Structural basis for the nuclear import of the human androgen receptor

ML Cutress, HC Whitaker, IG Mills… - Journal of cell …, 2008 - journals.biologists.com
ML Cutress, HC Whitaker, IG Mills, M Stewart, DE Neal
Journal of cell science, 2008journals.biologists.com
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 …
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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