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Sandbox Reserved 1103

TRF1 TRFH domain and TIN2 peptide complex, pdb=3BQOTRF1 TRFH domain and TIN2 peptide complex, pdb=3BQO

The TRFH (Telomeric Repeat Factor Homology) is a domain which is in the centre of the TRF1(Telomeric Repeat-Binding Factor) and of about 200 amino acids.In humans TERF1 is encoded by the TERF1 gene. TIN2(TERF1-interacting Nuclear Factor) is a protein encoded in humans by the TINF2 gene that can bind to TRFH TRF1.

<Structure load='Dimer2.pdb' size='350' frame='true' align='centre up' scene='82/829356/Dimer/3'>

FunctionFunction

TRF1TRF1 also called TERF1 is a protein part of the Shelterin complex (also called telosome) that has a crucial role in the regulation of telomeres [1]. TRF1 is an inhibitor of Telomerase, the protein that elongates telomeres. Indeed, when TRF1 is inactivated, telomeres are getting longer with no regulation. The TRFH (telomeric repeat factor homology 1h6o) domain is essential to the TRF1 because it’s the sequence where the protein dimerize to form a functional homodimer. Then, the protein can interact with DNA by fixing to the repeated sequence TTAGGG, and can then remodel DNA. This activity of remodeling is enhanced by the TIN2[2] . TIN2 or TINF2 (TERF1 interacting nuclear factor 2) is also a protein of the Shelterin that can bind to TRF1. It acts as a bridge or a link between TRF1 and TPP or TRF2 that are others proteins of the shelterin complex. This link will regulate their activity and can also stabilize TRF1’s interaction with DNA. When TIN2 is mutated, telomeres are no longer regulated. TRF1 alone doesn’t seems to be efficient to regulate Telomerase. Because of their function in telomeres regulation, TRF1 TIN2 are key proteins involved in cell aging and their dysfunction can directly leads to disease like cancer or other cell cycle diseases.

[xtra 1][xtra 2][xtra 3][xtra 4]

StructureStructure

The TRF1 TRFH domainThe TRF1 TRFH domain

The TRF1 TRFH domain is a sequence motif of about 200 amino acids located in the centre of TRF1. It is entirely constituted of α helices and binds to another TRF1 TRFH to form a homodimer. The two monomers are antiparallel and form a homodimer which is symmetrical. There are three α-helices from each monomer involved in this homodimerization: , . To form a dimer, the helix 1 of one monomer comes into contact with helix 1 of the other monomer, its helix 2 does it with the helix 2, and so does the helix 9. The two helices 9 stabilize the dimer interface and are perpendicular to the helices 1, forming a cross brace at the top and the bottom of it. The two helices 1 are the core of the dimer interface. This interface involves many hydrophobic interactions and a few hydrogen bonds. The amino acids of each helix 1 are central to the formation of the hydrophobic core. “Trp77 packs against (helix 9) within the monomer and between and and against of helix 9 from its partner” (Fairall L et al Mol Cell.[3]) The hydrogen bonds involved in the dimer interface are formed between of one monomer with of the other monomer. Overall, this dimer interface is highly hydrophobic and packed.

The TRF1 TRFH-TIN2 interactionThe TRF1 TRFH-TIN2 interaction

The interaction between TRF1 TRFH and the TIN2 peptide involves the C-terminus of the peptide which is called TIN2 TBM (TIN2-TRFH binding motif). TIN2 TBM is the sequence of the peptide that goes from amino acid 256 to the amino acid 276. In the homodimer of TRF1 TRFH, each TRF1 TRFH interacts with one TIN2 peptide. There are not many differences between the conformation of unliganded TRF1 TRFH and TRF1 TRFH bound to TIN2, the only one is the loop L34. When “TIN2 TBM is bound, loop L34 folds back upon helices 3 and 4, sandwiched between the helices and TIN2 TBM”. “The N-terminus of TIN2 TBM (H257-F-N-L-A-Phe262) adopts an extended conformation stabilized by an extensive intermolecular hydrogen-bonding network. The side chain of L260 is therefore positioned into a deep hydrophobic pocket of TRF1 TRFH. In addition, F258 and P262 also make hydrophobic contacts with TRF1 TRFH: F258 sits on concave surface, whereas P262 stacks with TRF1-F142.” (Chen Y et al Science [2]) C-terminus of TIN2 TBM (L263-G-R-R-R-V268) and D139-A-Q141 of TRF1 TRFH form an antiparallel β sheet. This arrangement positions the C-terminus of TIN2 TBM on the surface of loop L34, allowing R265-R-R267 of TIN2 TBM to be in contact with TRF1 TRFH through electrostatic interactions. “, R266 is nested within an acidic depression on the surface of loop L34 through a network of salt bridges and hydrogen bonds.” (Chen Y et al Science [2]) TIN2 TBM also has the sequence F-X-L-X-P at its N-terminus, the sequence F/Y-X-L-X-P being involved in the binding of several shelterin-associated proteins to TRF1 TRFH.


DiseaseDisease

Since TIN2 is a protein part of the shelterin complex that regulate the length of telomere, a mutation of the TINF2 gene can lead to alter the binding of TIN2 to TRF1, causing, telomeropathies: Dyskeratosis congenita and Revesz syndrome .

Dyskeratosis congenitaDyskeratosis congenita

Dyskeratosis congenita is a disorder which is characterised by bone marrow dysfunction, abnormality of the skin, mucocutaneous triad of oral leucoplakia, nail dystrophy, as well as a predisposition to cancer. TINF2 is one of the nine identified genes that when mutated are related to the Dyskeratosis congenita, the others being DKC1,TERC,TERT, NOP10, NHP2, C16orf57, TCAB1 and PARN. TIN2 mutations are imply in several different mechanims.

The majority of identified TIN2 dyskeratosis congenita mutations cluster is a highly conserved 30-amino-acid region near the ends of its TRF1 binding domain [4]. A disruption of this domain causes a loss of TRF1 binding to TIN2, resulting in a telomeric instability [5]. Another proposal is that TIN2 helps TPP1, another component of the shelterin complex, in the recruitment of telomerase through an unknown mechanism that is disrupted by the TIN2 dyskeratosis congenita mutations, leading once again to a telomeric instability [5] Finally, TIN2 seems to regulate the effect of the tankyrase 1, an poly ADP-ribose polymerase, by stabilising the formation of a TIN2–tankyrase 1–TRF1 complex. This prevent the binding of TRF1 to the telomere ends. In the case of amino acid mutations in TIN2 this might act by the same mechanism as a knock-down and leave telomere ends permanently unprotected, causing a shortening of telomere length [6].

Revesz syndromeRevesz syndrome

Revesz syndrome is characterised by bone marrow hypoplasia, nail dystrophy, growth retardation, exudative retinopathy, severe aplastic anemia [7]. Revesz syndrome also appears to be part of the DKC disease spectrum. Patients with Revesz syndrome have presented with heterozygous mutations in TINF2 gene which is located on chromosome 14q12 [5].

ReferencesReferences

  1. ↑ Veverka P, Janovic T, Hofr C. Quantitative Biology of Human Shelterin and Telomerase: Searching for the Weakest Point. Int J Mol Sci. 2019 Jun 28;20(13). pii: ijms20133186. doi: 10.3390/ijms20133186. PMID:31261825 doi:http://dx.doi.org/10.3390/ijms20133186
  2. ↑ 2.0 2.1 2.2 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
  3. ↑ Fairall L, Chapman L, Moss H, de Lange T, Rhodes D. Structure of the TRFH dimerization domain of the human telomeric proteins TRF1 and TRF2. Mol Cell. 2001 Aug;8(2):351-61. PMID:11545737
  4. ↑ Ye JZ, Donigian JR, van Overbeek M, Loayza D, Luo Y, Krutchinsky AN, Chait BT, de Lange T. TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres. J Biol Chem. 2004 Nov 5;279(45):47264-71. doi: 10.1074/jbc.M409047200. Epub 2004 , Aug 16. PMID:15316005 doi:http://dx.doi.org/10.1074/jbc.M409047200
  5. ↑ 5.0 5.1 5.2 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
  6. ↑ Kirwan M, Dokal I. Dyskeratosis congenita, stem cells and telomeres. Biochim Biophys Acta. 2009 Apr;1792(4):371-9. doi: 10.1016/j.bbadis.2009.01.010. , Epub 2009 Feb 7. PMID:19419704 doi:http://dx.doi.org/10.1016/j.bbadis.2009.01.010
  7. ↑ Riyaz A, Riyaz N, Jayakrishnan MP, Mohamed Shiras PT, Ajith Kumar VT, Ajith BS. Revesz syndrome. Indian J Pediatr. 2007 Sep;74(9):862-3. doi: 10.1007/s12098-007-0155-2. PMID:17901676 doi:http://dx.doi.org/10.1007/s12098-007-0155-2
  1. ↑ Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, de Lange T. Control of human telomere length by TRF1 and TRF2. Mol Cell Biol. 2000 Mar;20(5):1659-68. doi: 10.1128/mcb.20.5.1659-1668.2000. PMID:10669743 doi:http://dx.doi.org/10.1128/mcb.20.5.1659-1668.2000
  2. ↑ 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
  3. ↑ Chen Y. The structural biology of the shelterin complex. Biol Chem. 2019 Mar 26;400(4):457-466. doi: 10.1515/hsz-2018-0368. PMID:30352022 doi:http://dx.doi.org/10.1515/hsz-2018-0368
  4. ↑ Wallace HA, Rana V, Nguyen HQ, Bosco G. Condensin II subunit NCAPH2 associates with shelterin protein TRF1 and is required for telomere stability. J Cell Physiol. 2019 Nov;234(11):20755-20768. doi: 10.1002/jcp.28681. Epub 2019, Apr 26. PMID:31026066 doi:http://dx.doi.org/10.1002/jcp.28681

External RessourcesExternal Ressources

TERF1 in Wikipedia

TINF2 in Wikipedia

Shelterin in Wikipedia

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA, Marina Nzepa, Yona Steinberg, Salomé Leveque, Judith Weber
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