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3BQO TRF1 TRFH domain and TIN2 peptide complex'>
FunctionTRF1 also called TERF1 (Telomeric repeat-binding factor 1) is a protein part of the Shelterin complex (called also telosome) that has a crucial role in the regulation of telomeres [1]. TRF1 is an inhibitor of Telomerase, the protein that elongate 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 dimerizes 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. This link will regulated 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.
StructureThe 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[6] Structural highlightsReferences
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