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5h65

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Revision as of 11:34, 16 November 2017

Crystal structure of human POT1 and TPP1

Structural highlights

5h65 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	POT1 (HUMAN), ACD, PIP1, PTOP, TINT1, TPP1 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[POTE1_HUMAN] Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini. Is a component of the double-stranded telomeric DNA-binding TRF1 complex which is involved in the regulation of telomere length by cis-inhibition of telomerase. Also acts as a single-stranded telomeric DNA-binding protein and thus may act as a downstream effector of the TRF1 complex and may transduce information about telomere maintenance and/or length to the telomere terminus. 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. Binds to two or more telomeric single-stranded 5'-TTAGGG-3' repeats (G-strand) and with high specificity to a minimal telomeric single-stranded 5'-TAGGGTTAG-3' sequence. Binds telomeric single-stranded sequences internally or at proximity of a 3'-end. Its activity is TERT dependent but it does not increase TERT activity by itself. In contrast, the ACD-POT1 heterodimer enhances telomere elongation by increasing telomerase processivity.^[1] ^[2] ^[3] ^[4] ^[5] [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.^[6] ^[7] ^[8] ^[9] ^[10]

Publication Abstract from PubMed

Mammalian shelterin proteins POT1 and TPP1 form a stable heterodimer that protects chromosome ends and regulates telomerase-mediated telomere extension. However, how POT1 interacts with TPP1 remains unknown. Here we present the crystal structure of the C-terminal portion of human POT1 (POT1C) complexed with the POT1-binding motif of TPP1. The structure shows that POT1C contains two domains, a third OB fold and a Holliday junction resolvase-like domain. Both domains are essential for binding to TPP1. Notably, unlike the heart-shaped structure of ciliated protozoan Oxytricha nova TEBPalpha-beta complex, POT1-TPP1 adopts an elongated V-shaped conformation. In addition, we identify several missense mutations in human cancers that disrupt the POT1C-TPP1 interaction, resulting in POT1 instability. POT1C mutants that bind TPP1 localize to telomeres but fail to repress a DNA damage response and inappropriate repair by A-NHEJ. Our results reveal that POT1 C terminus is essential to prevent initiation of genome instability permissive for tumorigenesis.

Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer.,Chen C, Gu P, Wu J, Chen X, Niu S, Sun H, Wu L, Li N, Peng J, Shi S, Fan C, Huang M, Wong CC, Gong Q, Kumar-Sinha C, Zhang R, Pusztai L, Rai R, Chang S, Lei M Nat Commun. 2017 Apr 10;8:14929. doi: 10.1038/ncomms14929. PMID:28393832^[11]

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

References

↑ Colgin LM, Baran K, Baumann P, Cech TR, Reddel RR. Human POT1 facilitates telomere elongation by telomerase. Curr Biol. 2003 May 27;13(11):942-6. PMID:12781132
↑ Loayza D, De Lange T. POT1 as a terminal transducer of TRF1 telomere length control. Nature. 2003 Jun 26;423(6943):1013-8. Epub 2003 May 25. PMID:12768206 doi:10.1038/nature01688
↑ 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
↑ 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
↑ 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
↑ 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
↑ Chen C, Gu P, Wu J, Chen X, Niu S, Sun H, Wu L, Li N, Peng J, Shi S, Fan C, Huang M, Wong CC, Gong Q, Kumar-Sinha C, Zhang R, Pusztai L, Rai R, Chang S, Lei M. Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer. Nat Commun. 2017 Apr 10;8:14929. doi: 10.1038/ncomms14929. PMID:28393832 doi:http://dx.doi.org/10.1038/ncomms14929

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5h65"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5h65 is ON HOLD  until Paper Publication
+==Crystal structure of human POT1 and TPP1==
+<StructureSection load='5h65' size='340' side='right' caption='[[5h65]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5h65]] 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=5H65 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5H65 FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">POT1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), 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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5h65 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5h65 OCA], [http://pdbe.org/5h65 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5h65 RCSB], [http://www.ebi.ac.uk/pdbsum/5h65 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5h65 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/POTE1_HUMAN POTE1_HUMAN]] Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini. Is a component of the double-stranded telomeric DNA-binding TRF1 complex which is involved in the regulation of telomere length by cis-inhibition of telomerase. Also acts as a single-stranded telomeric DNA-binding protein and thus may act as a downstream effector of the TRF1 complex and may transduce information about telomere maintenance and/or length to the telomere terminus. 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. Binds to two or more telomeric single-stranded 5'-TTAGGG-3' repeats (G-strand) and with high specificity to a minimal telomeric single-stranded 5'-TAGGGTTAG-3' sequence. Binds telomeric single-stranded sequences internally or at proximity of a 3'-end. Its activity is TERT dependent but it does not increase TERT activity by itself. In contrast, the ACD-POT1 heterodimer enhances telomere elongation by increasing telomerase processivity.<ref>PMID:12781132</ref> <ref>PMID:12768206</ref> <ref>PMID:16166375</ref> <ref>PMID:17237768</ref> <ref>PMID:20231318</ref>  [[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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Mammalian shelterin proteins POT1 and TPP1 form a stable heterodimer that protects chromosome ends and regulates telomerase-mediated telomere extension. However, how POT1 interacts with TPP1 remains unknown. Here we present the crystal structure of the C-terminal portion of human POT1 (POT1C) complexed with the POT1-binding motif of TPP1. The structure shows that POT1C contains two domains, a third OB fold and a Holliday junction resolvase-like domain. Both domains are essential for binding to TPP1. Notably, unlike the heart-shaped structure of ciliated protozoan Oxytricha nova TEBPalpha-beta complex, POT1-TPP1 adopts an elongated V-shaped conformation. In addition, we identify several missense mutations in human cancers that disrupt the POT1C-TPP1 interaction, resulting in POT1 instability. POT1C mutants that bind TPP1 localize to telomeres but fail to repress a DNA damage response and inappropriate repair by A-NHEJ. Our results reveal that POT1 C terminus is essential to prevent initiation of genome instability permissive for tumorigenesis.
-Authors: Chen, C., Wu, J., Lei, M.
+Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer.,Chen C, Gu P, Wu J, Chen X, Niu S, Sun H, Wu L, Li N, Peng J, Shi S, Fan C, Huang M, Wong CC, Gong Q, Kumar-Sinha C, Zhang R, Pusztai L, Rai R, Chang S, Lei M Nat Commun. 2017 Apr 10;8:14929. doi: 10.1038/ncomms14929. PMID:28393832<ref>PMID:28393832</ref>
-Description: Crystal structure of human POT1 and TPP1
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5h65" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Human]]
+[[Category: Chen, C]]
 [[Category: Lei, M]]
 [[Category: Wu, J]]
-[[Category: Chen, C]]
+[[Category: Dna binding protein]]
+[[Category: Ob fold]]
+[[Category: Telomere]]

5h65

From Proteopedia

Revision as of 11:34, 16 November 2017

Crystal structure of human POT1 and TPP1

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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