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3bua

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3bua, resolution 2.50Å ()
Gene: TERF2, TRBF2, TRF2 (Homo sapiens), DCLRE1B, SNM1B (Homo sapiens)
Related: 3bu8, 3bqo
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Crystal Structure of TRF2 TRFH domain and APOLLO peptide complex

Publication Abstract from PubMed

Mammalian telomeres are protected by a six-protein complex, shelterin. Shelterin contains two closely related proteins, TRF1 and TRF2, which recruit various proteins to telomeres. Here we dissect the interactions of TRF1 and TRF2 with their shared binding partner, TIN2, and other shelterin accessory factors. TRF1 recognizes TIN2 using a conserved molecular surface in its TRF homology (TRFH) domain. However, this same surface does not act as a TIN2 binding site in TRF2, and TIN2 binding to TRF2 is mediated by a region outside the TRFH domain. Instead, the TRFH docking site of TRF2 binds a shelterin accessory factor Apollo, which does not interact with the TRFH domain of TRF1. Conversely, the TRFH domain of TRF1, but not of TRF2, interacts with another shelterin associated factor PinX1.

A Shared Docking Motif in TRF1 and TRF2 Used for Differential Recruitment of Telomeric Proteins., Chen Y, Yang Y, van Overbeek M, Donigian JR, Baciu P, de Lange T, Lei M, Science. 2008 Jan 17;. PMID:18202258

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

Disease

[DCR1B_HUMAN] Defects in DCLRE1B may be a cause of Hoyeraal-Hreidarsson syndrome (HHS) [MIM:300240]. HHS is a multisystem disorder affecting males and is characterized by aplastic anemia, immunodeficiency, microcephaly, cerebellar hypoplasia, and growth retardation. Note=An aberrant splice variant designated Apollo-Delta has been found in a patient with Hoyeraal-Hreidarsson syndrome. Apollo-Delta hampers the proper replication of telomeres, leading to major telomeric dysfunction and cellular senescence, but maintains its DNA interstrand cross-link repair function in the whole genome.[1]

Function

[TERF2_HUMAN] Binds the telomeric double-stranded 5'-TTAGGG-3' repeat and plays a central role in telomere maintenance and protection against end-to-end fusion of chromosomes. In addition to its telomeric DNA-binding role, required to recruit a number of factors and enzymes required for telomere protection, including the shelterin complex, TERF2IP/RAP1 and DCLRE1B/Apollo. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded 5'-TTAGGG-3' 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. Together with DCLRE1B/Apollo, plays a key role in telomeric loop (T loop) formation by generating 3' single-stranded overhang at the leading end telomeres: T loops have been proposed to protect chromosome ends from degradation and repair. Required both to recruit DCLRE1B/Apollo to telomeres and activate the exonuclease activity of DCLRE1B/Apollo. Preferentially binds to positive supercoiled DNA. Together with DCLRE1B/Apollo, required to control the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Recruits TERF2IP/RAP1 to telomeres, thereby participating in to repressing homology-directed repair (HDR), which can affect telomere length.[2] [3] [4] [DCR1B_HUMAN] 5'-3' exonuclease that plays a central role in telomere maintenance and protection during S-phase. Participates in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair, thereby ensuring that telomeres do not fuse. Plays a key role in telomeric loop (T loop) formation by being recruited by TERF2 at the leading end telomeres and by processing leading-end telomeres immediately after their replication via its exonuclease activity: generates 3' single-stranded overhang at the leading end telomeres avoiding blunt leading-end telomeres that are vulnerable to end-joining reactions and expose the telomere end in a manner that activates the DNA repair pathways. Together with TERF2, required to protect telomeres from replicative damage during replication by controlling the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Also involved in response to DNA damage: plays a role in response to DNA interstrand cross-links (ICLs) by facilitating double-strand break formation. In case of spindle stress, involved in prophase checkpoint.[5] [6] [7] [8] [9] [10] [11] [12] [13]

About this Structure

3bua is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  • Chen Y, Yang Y, van Overbeek M, Donigian JR, Baciu P, de Lange T, Lei M. A Shared Docking Motif in TRF1 and TRF2 Used for Differential Recruitment of Telomeric Proteins. Science. 2008 Jan 17;. PMID:18202258
  1. Touzot F, Callebaut I, Soulier J, Gaillard L, Azerrad C, Durandy A, Fischer A, de Villartay JP, Revy P. Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal-Hreidarsson syndrome. Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10097-102. doi:, 10.1073/pnas.0914918107. Epub 2010 May 17. PMID:20479256 doi:10.1073/pnas.0914918107
  2. van Steensel B, Smogorzewska A, de Lange T. TRF2 protects human telomeres from end-to-end fusions. Cell. 1998 Feb 6;92(3):401-13. PMID:9476899
  3. 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
  4. Ye J, Lenain C, Bauwens S, Rizzo A, Saint-Leger A, Poulet A, Benarroch D, Magdinier F, Morere J, Amiard S, Verhoeyen E, Britton S, Calsou P, Salles B, Bizard A, Nadal M, Salvati E, Sabatier L, Wu Y, Biroccio A, Londono-Vallejo A, Giraud-Panis MJ, Gilson E. TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage. Cell. 2010 Jul 23;142(2):230-42. doi: 10.1016/j.cell.2010.05.032. PMID:20655466 doi:10.1016/j.cell.2010.05.032
  5. Ishiai M, Kimura M, Namikoshi K, Yamazoe M, Yamamoto K, Arakawa H, Agematsu K, Matsushita N, Takeda S, Buerstedde JM, Takata M. DNA cross-link repair protein SNM1A interacts with PIAS1 in nuclear focus formation. Mol Cell Biol. 2004 Dec;24(24):10733-41. PMID:15572677 doi:24/24/10733
  6. Demuth I, Digweed M, Concannon P. Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation. Oncogene. 2004 Nov 11;23(53):8611-8. PMID:15467758 doi:1207895
  7. van Overbeek M, de Lange T. Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase. Curr Biol. 2006 Jul 11;16(13):1295-302. Epub 2006 May 25. PMID:16730176 doi:10.1016/j.cub.2006.05.022
  8. Lenain C, Bauwens S, Amiard S, Brunori M, Giraud-Panis MJ, Gilson E. The Apollo 5' exonuclease functions together with TRF2 to protect telomeres from DNA repair. Curr Biol. 2006 Jul 11;16(13):1303-10. Epub 2006 May 25. PMID:16730175 doi:10.1016/j.cub.2006.05.021
  9. Demuth I, Bradshaw PS, Lindner A, Anders M, Heinrich S, Kallenbach J, Schmelz K, Digweed M, Meyn MS, Concannon P. Endogenous hSNM1B/Apollo interacts with TRF2 and stimulates ATM in response to ionizing radiation. DNA Repair (Amst). 2008 Aug 2;7(8):1192-201. doi: 10.1016/j.dnarep.2008.03.020., Epub 2008 May 12. PMID:18468965 doi:10.1016/j.dnarep.2008.03.020
  10. Bae JB, Mukhopadhyay SS, Liu L, Zhang N, Tan J, Akhter S, Liu X, Shen X, Li L, Legerski RJ. Snm1B/Apollo mediates replication fork collapse and S Phase checkpoint activation in response to DNA interstrand cross-links. Oncogene. 2008 Aug 28;27(37):5045-56. doi: 10.1038/onc.2008.139. Epub 2008 May, 12. PMID:18469862 doi:10.1038/onc.2008.139
  11. Liu L, Akhter S, Bae JB, Mukhopadhyay SS, Richie CT, Liu X, Legerski R. SNM1B/Apollo interacts with astrin and is required for the prophase cell cycle checkpoint. Cell Cycle. 2009 Feb 15;8(4):628-38. Epub 2009 Feb 7. PMID:19197158
  12. Anders M, Mattow J, Digweed M, Demuth I. Evidence for hSNM1B/Apollo functioning in the HSP70 mediated DNA damage response. Cell Cycle. 2009 Jun 1;8(11):1725-32. Epub 2009 Jun 1. PMID:19411856
  13. Ye J, Lenain C, Bauwens S, Rizzo A, Saint-Leger A, Poulet A, Benarroch D, Magdinier F, Morere J, Amiard S, Verhoeyen E, Britton S, Calsou P, Salles B, Bizard A, Nadal M, Salvati E, Sabatier L, Wu Y, Biroccio A, Londono-Vallejo A, Giraud-Panis MJ, Gilson E. TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage. Cell. 2010 Jul 23;142(2):230-42. doi: 10.1016/j.cell.2010.05.032. PMID:20655466 doi:10.1016/j.cell.2010.05.032

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