| 3BQO TRF1 TRFH domain and TIN2 peptide complex'
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 . The two monomers are antiparallel and form a homodimer which is symmetrical. There are three α-helices from each monomer involved in this homodimerization: the helices 1, 2 and 9. 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 Trp77 of each helix 1 are central to the formation of the hydrophobic core. “Trp77 packs against Phe255 (helix 9) within the monomer and between Ala259 and Ala260 and against Val263 of helix 9 from its partner” (Fairall L et al Mol Cell.[3]) The hydrogen bonds involved in the dimer interface are formed between Glu71 of one monomer with Ser85 of the other monomer. Overall, this dimer interface is highly hydrophobic and packed.
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 [4]) 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 [5]) 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.
Disease
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Structural highlights
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- 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
- 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
- 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
- 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 Ressources
TERF1 in Wikipedia
TINF2 in Wikipedia
Shelterin in Wikipedia
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