Sandbox Reserved 1103
From Proteopedia
(Difference between revisions)
| Line 21: | Line 21: | ||
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 <ref>PMID:18202258</ref>) 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 <ref>PMID:18202258</ref>) 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 [https://en.wikipedia.org/wiki/Shelterin shelterin]-associated proteins to TRF1 TRFH. | 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 <ref>PMID:18202258</ref>) 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 <ref>PMID:18202258</ref>) 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 [https://en.wikipedia.org/wiki/Shelterin shelterin]-associated proteins to TRF1 TRFH. | ||
| + | |||
| + | Finally it has been shown that TIN2 appears to regulate the effect of the tankyrase 1, an poly ADP-ribose) polymerase | ||
| Line 31: | Line 33: | ||
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. | 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 [https://en.wikipedia.org/wiki/Dyskerin DKC1],[https://en.wikipedia.org/wiki/Telomerase_RNA_component TERC],[https://en.wikipedia.org/wiki/Telomerase_reverse_transcriptase TERT], NOP10, NHP2, C16orf57, TCAB1 and [https://en.wikipedia.org/wiki/Poly(A)-specific_ribonuclease PARN]. | + | TINF2 is one of the nine identified genes that when mutated are related to the Dyskeratosis congenita, the others being [https://en.wikipedia.org/wiki/Dyskerin DKC1],[https://en.wikipedia.org/wiki/Telomerase_RNA_component TERC],[https://en.wikipedia.org/wiki/Telomerase_reverse_transcriptase TERT], NOP10, NHP2, C16orf57, TCAB1 and [https://en.wikipedia.org/wiki/Poly(A)-specific_ribonuclease PARN]. TIN2 mutation 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 <ref>PMID: 15316005 </ref>, from position 270 to 300, located eight amino acids C-terminal to the FxLxP motif. A disrutpion of this domain causes a loss of TRF1 binding to TIN2, resulting in a telomeric instability<ref>PMID: 18252230 </ref>. Another proposal is that TIN2 help 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 <ref>PMID: 18252230 </ref>. | + | 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 <ref>PMID: 15316005 </ref>, from position 270 to 300, located eight amino acids C-terminal to the FxLxP motif. A disrutpion of this domain causes a loss of TRF1 binding to TIN2, resulting in a telomeric instability<ref>PMID: 18252230 </ref>. |
| + | Another proposal is that TIN2 help 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 <ref>PMID: 18252230 </ref>. | ||
| + | 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 <ref>PMID: 19419704 </ref>. | ||
=== Revesz syndrome === | === Revesz syndrome === | ||
| Line 47: | Line 51: | ||
{{Wikipedia|TERF1}} | {{Wikipedia|TERF1}} | ||
{{Wikipedia|TINF2}} | {{Wikipedia|TINF2}} | ||
| - | {{Wikipedia|Shelterin | + | {{Wikipedia|Shelterin} |
Revision as of 21:06, 16 January 2020
TRF1 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.
| |||||||||||
