View source for 4b18


==The crystal structure of human Importin alpha 5 with TERT NLS peptide==
<StructureSection load='4b18' size='340' side='right'caption='[[4b18]], [[Resolution|resolution]] 2.52&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4b18]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B18 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B18 FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2bck|2bck]], [[2jdq|2jdq]]</div></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/RNA-directed_DNA_polymerase RNA-directed DNA polymerase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.49 2.7.7.49] </span></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=4b18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b18 OCA], [https://pdbe.org/4b18 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b18 RCSB], [https://www.ebi.ac.uk/pdbsum/4b18 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b18 ProSAT]</span></td></tr>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/TERT_HUMAN TERT_HUMAN]] Note=Activation of telomerase has been implicated in cell immortalization and cancer cell pathogenesis.  Defects in TERT are associated with susceptibilty to aplastic anemia (AA) [MIM:[https://omim.org/entry/609135 609135]]. AA is a rare disease in which the reduction of the circulating blood cells results from damage to the stem cell pool in bone marrow. In most patients, the stem cell lesion is caused by an autoimmune attack. T-lymphocytes, activated by an endogenous or exogenous, and most often unknown antigenic stimulus, secrete cytokines, including IFN-gamma, which would in turn be able to suppress hematopoiesis.<ref>PMID:15885610</ref> <ref>PMID:16627250</ref> <ref>PMID:16990594</ref> <ref>PMID:19760749</ref>   Note=Genetic variations in TERT are associated with coronary artery disease (CAD).<ref>PMID:16890917</ref>   Defects in TERT are the cause of dyskeratosis congenita autosomal dominant type 2 (DKCA2) [MIM:[https://omim.org/entry/613989 613989]]. A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy.<ref>PMID:15885610</ref> <ref>PMID:16247010</ref>   Defects in TERT are the cause of pulmonary fibrosis, and/or bone marrow failure, telomere-related, type 1 (PFBMFT1) [MIM:[https://omim.org/entry/614742 614742]]. A disease associated with shortened telomeres. Pulmonary fibrosis is the most common manifestation. Other manifestations include aplastic anemia due to bone marrow failure, hepatic fibrosis, and increased cancer risk, particularly myelodysplastic syndrome and acute myeloid leukemia. Phenotype, age at onset, and severity are determined by telomere length. infections, fatal pulmonary complications, or malignancy.<ref>PMID:15814878</ref> <ref>PMID:17460043</ref> <ref>PMID:21436073</ref> <ref>PMID:21483807</ref> <ref>PMID:22512499</ref>   Defects in TERT are the cause of dyskeratosis congenita autosomal recessive type 4 (DKCB4) [MIM:[https://omim.org/entry/613989 613989]]. A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy.  Defects in TERT are a cause of susceptibility to pulmonary fibrosis idiopathic (IPF) [MIM:[https://omim.org/entry/178500 178500]]. Pulmonary fibrosis is a lung disease characterized by shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying degrees of inflammation and fibrosis on biopsy. It results in acute lung injury with subsequent scarring and endstage lung disease. 
== Function ==
[[https://www.uniprot.org/uniprot/IMA1_HUMAN IMA1_HUMAN]] 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. [[https://www.uniprot.org/uniprot/TERT_HUMAN TERT_HUMAN]] Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes. Active in progenitor and cancer cells. Inactive, or very low activity, in normal somatic cells. Catalytic component of the teleromerase holoenzyme complex whose main activity is the elongation of telomeres by acting as a reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. Catalyzes the RNA-dependent extension of 3'-chromosomal termini with the 6-nucleotide telomeric repeat unit, 5'-TTAGGG-3'. The catalytic cycle involves primer binding, primer extension and release of product once the template boundary has been reached or nascent product translocation followed by further extension. More active on substrates containing 2 or 3 telomeric repeats. Telomerase activity is regulated by a number of factors including telomerase complex-associated proteins, chaperones and polypeptide modifiers. Modulates Wnt signaling. Plays important roles in aging and antiapoptosis.<ref>PMID:9389643</ref> <ref>PMID:14963003</ref> <ref>PMID:15082768</ref> <ref>PMID:15857955</ref> <ref>PMID:17026956</ref> <ref>PMID:17548608</ref> <ref>PMID:17296728</ref> <ref>PMID:17264120</ref> <ref>PMID:19188162</ref> <ref>PMID:19567472</ref> <ref>PMID:19571879</ref> <ref>PMID:19777057</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Telomeres are essential for chromosome integrity and protection, and their maintenance requires the ribonucleoprotein enzyme telomerase. Previously, we have shown that human telomerase reverse transcriptase (hTERT) contains a bipartite nuclear localization signal (NLS; residues 222-240) that is responsible for nuclear import, and that Akt-mediated phosphorylation of residue S227 is important for efficient nuclear import of hTERT. Here, we show that hTERT binds to importin-alpha proteins through the bipartite NLS and that this heterodimer then forms a complex with importin-beta proteins to interact with the nuclear pore complex. Depletion of individual importin-alpha proteins results in a failure of hTERT nuclear import, and the resulting cytoplasmic hTERT is degraded by ubiquitin-dependent proteolysis. Crystallographic analysis reveals that the bipartite NLS interacts with both the major and minor sites of importin-alpha proteins. We also show that Akt-mediated phosphorylation of S227 increases the binding affinity for importin-alpha proteins and promotes nuclear import of hTERT, thereby resulting in increased telomerase activity. These data provide details of a binding mechanism that enables hTERT to interact with the nuclear import receptors and of the control of the dynamic nuclear transport of hTERT through phosphorylation.

Akt-mediated phosphorylation increases the binding affinity of hTERT for importin alpha to promote nuclear translocation.,Jeong SA, Kim K, Lee JH, Cha JS, Khadka P, Cho HS, Chung IK J Cell Sci. 2015 Jun 15;128(12):2287-301. doi: 10.1242/jcs.166132. Epub 2015 May , 21. PMID:25999477<ref>PMID:25999477</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4b18" style="background-color:#fffaf0;"></div>

==See Also==
*[[Importin 3D structures|Importin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: RNA-directed DNA polymerase]]
[[Category: Cho, H S]]
[[Category: Kim, K L]]
[[Category: Yoo, J H]]
[[Category: Transport protein - peptide complex]]