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| | <StructureSection load='5i2x' size='340' side='right'caption='[[5i2x]], [[Resolution|resolution]] 3.00Å' scene=''> | | <StructureSection load='5i2x' size='340' side='right'caption='[[5i2x]], [[Resolution|resolution]] 3.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5i2x]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5I2X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5I2X FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5i2x]] is a 2 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=5I2X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5I2X FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2i46|2i46]], [[5i2y|5i2y]]</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACD, PIP1, PTOP, TINT1, TPP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5i2x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i2x OCA], [https://pdbe.org/5i2x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5i2x RCSB], [https://www.ebi.ac.uk/pdbsum/5i2x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5i2x ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5i2x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i2x OCA], [http://pdbe.org/5i2x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i2x RCSB], [http://www.ebi.ac.uk/pdbsum/5i2x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5i2x ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ACD_HUMAN ACD_HUMAN]] Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Promotes binding of POT1 to single-stranded telomeric DNA. Modulates the inhibitory effects of POT1 on telomere elongation. The ACD-POT1 heterodimer enhances telomere elongation by increasing telomerase processivity. Plays a role in shelterin complex assembly. May play a role in organogenesis.<ref>PMID:15181449</ref> <ref>PMID:16166375</ref> <ref>PMID:16880378</ref> <ref>PMID:20231318</ref> <ref>PMID:17237768</ref> | + | [https://www.uniprot.org/uniprot/ACD_HUMAN ACD_HUMAN] Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Promotes binding of POT1 to single-stranded telomeric DNA. Modulates the inhibitory effects of POT1 on telomere elongation. The ACD-POT1 heterodimer enhances telomere elongation by increasing telomerase processivity. Plays a role in shelterin complex assembly. May play a role in organogenesis.<ref>PMID:15181449</ref> <ref>PMID:16166375</ref> <ref>PMID:16880378</ref> <ref>PMID:20231318</ref> <ref>PMID:17237768</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Nandakumar, J]] | + | [[Category: Nandakumar J]] |
| - | [[Category: Smith, E]] | + | [[Category: Smith E]] |
| - | [[Category: Ob fold]]
| + | |
| - | [[Category: Protein binding]]
| + | |
| Structural highlights
Function
ACD_HUMAN Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Promotes binding of POT1 to single-stranded telomeric DNA. Modulates the inhibitory effects of POT1 on telomere elongation. The ACD-POT1 heterodimer enhances telomere elongation by increasing telomerase processivity. Plays a role in shelterin complex assembly. May play a role in organogenesis.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Telomerase replicates chromosome ends to facilitate continued cell division. Mutations that compromise telomerase function result in stem cell failure diseases, such as dyskeratosis congenita (DC). One such mutation (K170Delta), residing in the telomerase-recruitment factor TPP1, provides an excellent opportunity to structurally, biochemically, and genetically dissect the mechanism of such diseases. We show through site-directed mutagenesis and X-ray crystallography that this TPP1 disease mutation deforms the conformation of two critical amino acids of the TEL [TPP1's glutamate (E) and leucine-rich (L)] patch, the surface of TPP1 that binds telomerase. Using CRISPR-Cas9 technology, we demonstrate that introduction of this mutation in a heterozygous manner is sufficient to shorten telomeres in human cells. Our findings rule out dominant-negative effects of the mutation. Instead, these findings implicate reduced TEL patch dosage in causing telomere shortening. Our studies provide mechanistic insight into telomerase-deficiency diseases and encourage the development of gene therapies to counter such diseases.
Structural and functional consequences of a disease mutation in the telomere protein TPP1.,Bisht K, Smith EM, Tesmer VM, Nandakumar J Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):13021-13026. Epub 2016 Nov 2. PMID:27807141[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Liu D, Safari A, O'Connor MS, Chan DW, Laegeler A, Qin J, Songyang Z. PTOP interacts with POT1 and regulates its localization to telomeres. Nat Cell Biol. 2004 Jul;6(7):673-80. Epub 2004 Jun 6. PMID:15181449 doi:http://dx.doi.org/10.1038/ncb1142
- ↑ de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005 Sep 15;19(18):2100-10. PMID:16166375 doi:10.1101/gad.1346005
- ↑ O'Connor MS, Safari A, Xin H, Liu D, Songyang Z. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):11874-9. Epub 2006 Jul 31. PMID:16880378 doi:0605303103
- ↑ Zaug AJ, Podell ER, Nandakumar J, Cech TR. Functional interaction between telomere protein TPP1 and telomerase. Genes Dev. 2010 Mar 15;24(6):613-22. doi: 10.1101/gad.1881810. PMID:20231318 doi:10.1101/gad.1881810
- ↑ Wang F, Podell ER, Zaug AJ, Yang Y, Baciu P, Cech TR, Lei M. The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature. 2007 Feb 1;445(7127):506-10. Epub 2007 Jan 21. PMID:17237768 doi:nature05454
- ↑ Bisht K, Smith EM, Tesmer VM, Nandakumar J. Structural and functional consequences of a disease mutation in the telomere protein TPP1. Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):13021-13026. Epub 2016 Nov 2. PMID:27807141 doi:http://dx.doi.org/10.1073/pnas.1605685113
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