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3bu8

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3bu8, resolution 2.15Å ()
Gene: TERF2, TRBF2, TRF2 (Homo sapiens), TINF2, TIN2 (Homo sapiens)
Related: 3bua, 3bqo
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Crystal Structure of TRF2 TRFH domain and TIN2 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

[TINF2_HUMAN] Defects in TINF2 are a cause of dyskeratosis congenita autosomal dominant type 3 (DKCA3) [MIM:613990]. 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.[1] Defects in TINF2 are a cause of retinopathy exudative with bone marrow failure (ERBMF) [MIM:268130]; also known as Revesz syndrome. ERBMF is characterized by bilateral exudative retinopathy, bone marrow hypoplasia, nail dystrophy, fine hair, cerebellar hypoplasia, and growth retardation.[2]

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.[3] [4] [5] [TINF2_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. Plays a role in shelterin complex assembly. Isoform 1 may have additional role in tethering telomeres to the nuclear matrix.[6] [7] [8]

About this Structure

3bu8 is a 4 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. Savage SA, Giri N, Baerlocher GM, Orr N, Lansdorp PM, Alter BP. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet. 2008 Feb;82(2):501-9. Epub 2008 Jan 31. PMID:18252230 doi:S0002-9297(08)00076-1
  2. Savage SA, Giri N, Baerlocher GM, Orr N, Lansdorp PM, Alter BP. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet. 2008 Feb;82(2):501-9. Epub 2008 Jan 31. PMID:18252230 doi:S0002-9297(08)00076-1
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Kaminker PG, Kim SH, Desprez PY, Campisi J. A novel form of the telomere-associated protein TIN2 localizes to the nuclear matrix. Cell Cycle. 2009 Mar 15;8(6):931-9. Epub 2009 Mar 26. PMID:19229133

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