Sandbox Reserved 1103
From Proteopedia
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== Function == | == Function == | ||
| - | [https://en.wikipedia.org/wiki/TERF1 TRF1]TRF1 also called [https://en.wikipedia.org/wiki/TERF1 TERF1] | + | [https://en.wikipedia.org/wiki/TERF1 TRF1]TRF1 also called [https://en.wikipedia.org/wiki/TERF1 TERF1] is a protein part of the [https://en.wikipedia.org/wiki/Shelterin Shelterin] complex (also called telosome) that has a crucial role in the regulation of telomeres <ref>PMID: 31261825</ref>. 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<ref>PMID: 18202258</ref> . TIN2 or [https://en.wikipedia.org/wiki/TINF2 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 [https://en.wikipedia.org/wiki/TERF2 TRF2] that are others proteins of the shelterin complex. This link will regulate their activity and can also stabilize TRF1’s interaction with DNA. | 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<ref>PMID: 18202258</ref> . TIN2 or [https://en.wikipedia.org/wiki/TINF2 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 [https://en.wikipedia.org/wiki/TERF2 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]]. | When TIN2 is mutated, telomeres are no longer regulated. TRF1 alone doesn’t seems to be efficient to regulate [[Telomerase]]. | ||
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== Structure == | == Structure == | ||
| - | The [https://en.wikipedia.org/wiki/TERF1 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: <scene name='82/829356/Helices_1/1'>the helices 1</scene>, <scene name='82/829356/Helices_2/1'>2</scene> <scene name='82/829356/Helices_9/1'>9</scene>. 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 <scene name='82/829356/Trp77/3'>Trp77</scene> of each helix 1 are central to the formation of the hydrophobic core. “Trp77 packs against <scene name='82/829356/Phe255/1'>Phe255</scene> (helix 9) within the monomer and between <scene name='82/829356/Ala259/1'>Ala259</scene> and <scene name='82/829356/Ala259/1'>Ala260</scene> and against Val263 of helix 9 from its partner” (Fairall L et al Mol Cell.<ref>PMID: 11545737</ref>) 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 [https://en.wikipedia.org/wiki/TERF1 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: <scene name='82/829356/Helices_1/1'>the helices 1</scene>, <scene name='82/829356/Helices_2/1'>2</scene> <scene name='82/829356/Helices_9/1'>9</scene>. 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 <scene name='82/829356/Trp77/3'>Trp77</scene> of each helix 1 are central to the formation of the hydrophobic core. “Trp77 packs against <scene name='82/829356/Phe255/1'>Phe255</scene> (helix 9) within the monomer and between <scene name='82/829356/Ala259/1'>Ala259</scene> and <scene name='82/829356/Ala259/1'>Ala260</scene> and against <scene name='82/829356/Val263/1'>Val263</scene> of helix 9 from its partner” (Fairall L et al Mol Cell.<ref>PMID: 11545737</ref>) The hydrogen bonds involved in the dimer interface are formed between <scene name='82/829356/Glu71/1'>Glu71</scene> of one monomer with <scene name='82/829356/Ser85/1'>Ser85</scene> of the other monomer. Overall, this dimer interface is highly hydrophobic and packed. |
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TIN2 is one of the nine identified genes that when mutated are related to the Dyskeratosis congenita, the others being DKC1, TERC, TERT, NOP10, NHP2, TIN2, C16orf57, TCAB1 and PARN. | TIN2 is one of the nine identified genes that when mutated are related to the Dyskeratosis congenita, the others being DKC1, TERC, TERT, NOP10, NHP2, TIN2, C16orf57, TCAB1 and PARN. | ||
| - | The mutated region of TIN2 in Dyskeratosis congenita patients is situated near the ends of its TRF1 binding domain. The majority of identified TIN2-DC mutations cluster | + | The mutated region of TIN2 in Dyskeratosis congenita patients is situated near the ends of its TRF1 binding domain. The majority of identified TIN2-DC mutations cluster is a highly conserved 30-amino-acid region from position 270 to 300, located eight amino acids C-terminal to the FxLxP motif that mediates binding of TIN2 to TRF1 <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-DC mutations, including K280E <ref>PMID: 18202258 </ref> <ref>PMID: 18252230 </ref>. |
=== Revesz syndrome === | === Revesz syndrome === | ||
| - | Revesz syndrome is | + | Revesz syndrome is characterised by bone marrow <ref>PMID: 17901676 </ref>. Revesz syndrome is according to some researcher 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. There is no treatment for this disease yet. |
== References == | == References == | ||
Revision as of 19:38, 15 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.
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