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{{STRUCTURE_3btr|  PDB=3btr  |  SCENE=  }}
===AR-NLS:Importin-alpha complex===
{{ABSTRACT_PUBMED_18319300}}


==Disease==
==AR-NLS:Importin-alpha complex==
[[http://www.uniprot.org/uniprot/ANDR_HUMAN ANDR_HUMAN]] Defects in AR are the cause of androgen insensitivity syndrome (AIS) [MIM:[http://omim.org/entry/300068 300068]]; previously known as testicular feminization syndrome (TFM). AIS is an X-linked recessive form of pseudohermaphroditism due end-organ resistance to androgen. Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal 46,XY karyotype.<ref>PMID:2594783</ref><ref>PMID:8413310</ref><ref>PMID:1775137</ref><ref>PMID:16129672</ref><ref>PMID:2082179</ref><ref>PMID:1999491</ref><ref>PMID:1609793</ref><ref>PMID:1426313</ref><ref>PMID:1487249</ref><ref>PMID:1307250</ref><ref>PMID:1569163</ref><ref>PMID:1464650</ref><ref>PMID:1430233</ref><ref>PMID:1316540</ref><ref>PMID:1480178</ref><ref>PMID:8224266</ref><ref>PMID:8103398</ref><ref>PMID:8281140</ref><ref>PMID:8325950</ref><ref>PMID:8096390</ref><ref>PMID:8446106</ref>[:]<ref>PMID:8162033</ref><ref>PMID:7981687</ref><ref>PMID:7981689</ref><ref>PMID:7962294</ref><ref>PMID:8040309</ref><ref>PMID:7929841</ref><ref>PMID:7993455</ref><ref>PMID:7970939</ref><ref>PMID:8830623</ref><ref>PMID:7641413</ref><ref>PMID:7671849</ref><ref>PMID:7633398</ref><ref>PMID:7537149</ref><ref>PMID:7581399</ref><ref>PMID:8723113</ref><ref>PMID:9039340</ref><ref>PMID:9001799</ref><ref>PMID:8626869</ref><ref>PMID:8768864</ref><ref>PMID:8918984</ref><ref>PMID:8683794</ref><ref>PMID:8647313</ref><ref>PMID:8809734</ref><ref>PMID:9106550</ref><ref>PMID:9160185</ref><ref>PMID:9007482</ref><ref>PMID:8990010</ref><ref>PMID:9255042</ref><ref>PMID:9252933</ref><ref>PMID:9328206</ref><ref>PMID:9302173</ref><ref>PMID:9544375</ref><ref>PMID:9698822</ref><ref>PMID:9788719</ref><ref>PMID:9610419</ref><ref>PMID:9856504</ref><ref>PMID:9554754</ref>[:]<ref>PMID:9851768</ref><ref>PMID:9627582</ref><ref>PMID:10571951</ref><ref>PMID:10221692</ref><ref>PMID:10404311</ref><ref>PMID:10022458</ref><ref>PMID:10221770</ref><ref>PMID:10590024</ref><ref>PMID:10458483</ref><ref>PMID:10690872</ref><ref>PMID:11587068</ref><ref>PMID:11744994</ref><ref>PMID:16595706</ref> Defects in AR are the cause of spinal and bulbar muscular atrophy X-linked type 1 (SMAX1) [MIM:[http://omim.org/entry/313200 313200]]; also known as Kennedy disease. SMAX1 is an X-linked recessive form of spinal muscular atrophy. Spinal muscular atrophy refers to a group of neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAX1 occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. It is characterized by slowly progressive limb and bulbar muscle weakness with fasciculations, muscle atrophy, and gynecomastia. The disorder is clinically similar to classic forms of autosomal spinal muscular atrophy. Note=Caused by trinucleotide CAG repeat expansion. In SMAX1 patients the number of Gln ranges from 38 to 62. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.<ref>PMID:15851746</ref>  Note=Defects in AR may play a role in metastatic prostate cancer. The mutated receptor stimulates prostate growth and metastases development despite of androgen ablation. This treatment can reduce primary and metastatic lesions probably by inducing apoptosis of tumor cells when they express the wild-type receptor. Defects in AR are the cause of androgen insensitivity syndrome partial (PAIS) [MIM:[http://omim.org/entry/312300 312300]]; also known as Reifenstein syndrome. PAIS is characterized by hypospadias, hypogonadism, gynecomastia, genital ambiguity, normal XY karyotype, and a pedigree pattern consistent with X-linked recessive inheritance. Some patients present azoospermia or severe oligospermia without other clinical manifestations.  
<StructureSection load='3btr' size='340' side='right'caption='[[3btr]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3btr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BTR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BTR FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3btr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3btr OCA], [https://pdbe.org/3btr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3btr RCSB], [https://www.ebi.ac.uk/pdbsum/3btr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3btr ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/IMA1_MOUSE IMA1_MOUSE] Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bt/3btr_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3btr ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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 5alpha-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-angstroms-resolution crystal structure of the importin-alpha-AR-NLS 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.


==Function==
Structural basis for the nuclear import of the human androgen receptor.,Cutress ML, Whitaker HC, Mills IG, Stewart M, Neal DE J Cell Sci. 2008 Apr 1;121(Pt 7):957-68. Epub 2008 Mar 4. PMID:18319300<ref>PMID:18319300</ref>
[[http://www.uniprot.org/uniprot/IMA2_MOUSE IMA2_MOUSE]] Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. [[http://www.uniprot.org/uniprot/ANDR_HUMAN ANDR_HUMAN]] Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.<ref>PMID:14664718</ref><ref>PMID:18084323</ref><ref>PMID:19345326</ref><ref>PMID:20980437</ref><ref>PMID:15563469</ref><ref>PMID:17591767</ref><ref>PMID:17911242</ref>  


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[3btr]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BTR OCA].
</div>
<div class="pdbe-citations 3btr" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
<references group="xtra"/><references/>
*[[Importin 3D structures|Importin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Mus musculus]]
[[Category: Cutress, M L.]]
[[Category: Cutress ML]]
[[Category: Mills, I G.]]
[[Category: Mills IG]]
[[Category: Neal, D E.]]
[[Category: Neal DE]]
[[Category: Stewart, M.]]
[[Category: Stewart M]]
[[Category: Whitaker, H C.]]
[[Category: Whitaker HC]]
[[Category: Disease mutation]]
[[Category: Dna-binding]]
[[Category: Hormone]]
[[Category: Importin-alpha-androgen receptor complex]]
[[Category: Lipid-binding]]
[[Category: Metal-binding]]
[[Category: Nucleus]]
[[Category: Phosphoprotein]]
[[Category: Protein transport]]
[[Category: Steroid-binding]]
[[Category: Transcription]]
[[Category: Transcription regulation]]
[[Category: Transport]]
[[Category: Zinc-finger]]

Latest revision as of 17:51, 1 November 2023

AR-NLS:Importin-alpha complexAR-NLS:Importin-alpha complex

Structural highlights

3btr is a 2 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.6Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IMA1_MOUSE Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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 5alpha-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-angstroms-resolution crystal structure of the importin-alpha-AR-NLS 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.

Structural basis for the nuclear import of the human androgen receptor.,Cutress ML, Whitaker HC, Mills IG, Stewart M, Neal DE J Cell Sci. 2008 Apr 1;121(Pt 7):957-68. Epub 2008 Mar 4. PMID:18319300[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Cutress ML, Whitaker HC, Mills IG, Stewart M, Neal DE. Structural basis for the nuclear import of the human androgen receptor. J Cell Sci. 2008 Apr 1;121(Pt 7):957-68. Epub 2008 Mar 4. PMID:18319300 doi:http://dx.doi.org/jcs.022103

3btr, resolution 2.60Å

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