7trd
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| - | ==== | + | ==Human telomerase catalytic core structure at 3.3 Angstrom== |
| - | <StructureSection load='7trd' size='340' side='right'caption='[[7trd]]' scene=''> | + | <StructureSection load='7trd' size='340' side='right'caption='[[7trd]], [[Resolution|resolution]] 3.30Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7trd]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TRD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TRD FirstGlance]. <br> |
| - | </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=7trd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7trd OCA], [https://pdbe.org/7trd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7trd RCSB], [https://www.ebi.ac.uk/pdbsum/7trd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7trd ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.3Å</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=7trd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7trd OCA], [https://pdbe.org/7trd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7trd RCSB], [https://www.ebi.ac.uk/pdbsum/7trd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7trd ProSAT]</span></td></tr> | ||
</table> | </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/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 == | ||
| + | Human telomerase is a RNA-protein complex that extends the 3' end of linear chromosomes by synthesizing multiple copies of the telomeric repeat TTAGGG(1). Its activity is a determinant of cancer progression, stem cell renewal and cellular aging(2-5). Telomerase is recruited to telomeres and activated for telomere repeat synthesis by the telomere shelterin protein TPP1(6,7). Human telomerase has a bilobal structure with a catalytic core ribonuclear protein and a H and ACA box ribonuclear protein(8,9). Here we report cryo-electron microscopy structures of human telomerase catalytic core of telomerase reverse transcriptase (TERT) and telomerase RNA (TER (also known as hTR)), and of telomerase with the shelterin protein TPP1. TPP1 forms a structured interface with the TERT-unique telomerase essential N-terminal domain (TEN) and the telomerase RAP motif (TRAP) that are unique to TERT, and conformational dynamics of TEN-TRAP are damped upon TPP1 binding, defining the requirements for recruitment and activation. The structures further reveal that the elements of TERT and TER that are involved in template and telomeric DNA handling-including the TEN domain and the TRAP-thumb helix channel-are largely structurally homologous to those in Tetrahymena telomerase(10), and provide unique insights into the mechanism of telomerase activity. The binding site of the telomerase inhibitor BIBR1532(11,12) overlaps a critical interaction between the TER pseudoknot and the TERT thumb domain. Numerous mutations leading to telomeropathies(13,14) are located at the TERT-TER and TEN-TRAP-TPP1 interfaces, highlighting the importance of TER-TERT and TPP1 interactions for telomerase activity, recruitment and as drug targets. | ||
| + | |||
| + | Structure of active human telomerase with telomere shelterin protein TPP1.,Liu B, He Y, Wang Y, Song H, Zhou ZH, Feigon J Nature. 2022 Apr;604(7906):578-583. doi: 10.1038/s41586-022-04582-8. Epub 2022 , Apr 13. PMID:35418675<ref>PMID:35418675</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7trd" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Telomerase 3D structures|Telomerase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: | + | [[Category: Feigon J]] |
| + | [[Category: He Y]] | ||
| + | [[Category: Liu B]] | ||
| + | [[Category: Song H]] | ||
| + | [[Category: Wang Y]] | ||
| + | [[Category: Zhou ZH]] | ||
Current revision
Human telomerase catalytic core structure at 3.3 Angstrom
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Categories: Homo sapiens | Large Structures | Feigon J | He Y | Liu B | Song H | Wang Y | Zhou ZH
