Structural basis for the nuclear import of the human androgen receptor
Structural basis for the nuclear import of the human androgen receptor
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DOI：
10.1242/jcs.022103
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发表时间：
2008-04-01
影响因子：
4
通讯作者：
Neal, David E.
中科院分区：
文献类型：
--
作者：
Cutress, Mark L.;Whitaker, Hayley C.;Neal, David E.
配体依赖性核输入对于雄激素受体（AR）在健康和疾病中的功能至关重要。未配体的AR保留在细胞质中，但在结合5 α-二氢睾酮时，它易位到细胞核中并改变其靶基因的转录。AR的核输入由核输入因子输入素-α介导，其作为识别并结合货物蛋白上的特异性核定位信号（NLS）基序的受体起作用。我们在这里表明，AR直接结合importin-alpha，尽管比SV 40或核质蛋白的NLS更弱。我们描述了2.6埃分辨率的晶体结构的importin-alpha-ARNLS复合物，并表明，AR结合的主要NLS结合位点的importin-alpha的方式不同于大多数其他NLS。最后，我们已经表明，与前列腺癌和雄激素不敏感综合征相关的AR的NLS内的病理性突变降低了与importin-α的结合亲和力，随后延迟核输入;然而，令人惊讶的是，这些突变体的转录活性变化很大。因此，除了其在AR的核输入中的功能之外，AR的铰链区中的NLS在反式激活中具有单独的、相当独特的作用，一旦核输入已经实现，这就变得明显。
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.