期刊
JOURNAL OF CELL SCIENCE
卷 121, 期 7, 页码 957-968出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.022103
关键词
androgen-insensitivity syndrome; androgen receptor; nuclear import; prostate cancer
类别
资金
- Cancer Research UK Funding Source: Medline
- Medical Research Council [MC_U105178939, G0500966] Funding Source: Medline
- Wellcome Trust [080522] Funding Source: Medline
- Department of Health Funding Source: Medline
- MRC [MC_U105178939, G0500966] Funding Source: UKRI
- Medical Research Council [MC_U105178939, G0500966] Funding Source: researchfish
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 alpha-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-angstrom-resolution crystal structure of the importin-alpha-ARNLS 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.
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