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| - | [[Image:1fex.gif|left|200px]]<br /> | |
| - | <applet load="1fex" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1fex" /> | |
| - | '''SOLUTION STRUCTURE OF MYB-DOMAIN OF HUMAN RAP1'''<br /> | |
| | | | |
| - | ==Overview== | + | ==SOLUTION STRUCTURE OF MYB-DOMAIN OF HUMAN RAP1== |
| - | Mammalian telomeres are composed of long tandem arrays of double-stranded, telomeric TTAGGG repeats associated with the telomeric DNA-binding, proteins, TRF1 and TRF2. TRF1 and TRF2 contain a similar C-terminal Myb, domain that mediates sequence-specific binding to telomeric DNA. In the, budding yeast, telomeric DNA is associated with scRap1p, which has a, central DNA-binding domain that contains two structurally related Myb, domains connected by a long linker, an N-terminal BRCT domain, and a, C-terminal RCT domain. Recently, the human ortholog of scRap1p (hRap1) was, identified and shown to contain a BRCT domain and an RCT domain similar to, scRap1p. However, hRap1 contained only one recognizable Myb motif in the, center of the protein. Furthermore, while scRap1p binds telomeric DNA, directly, hRap1 has no DNA-binding ability. Instead, hRap1 is tethered to, telomeres by TRF2. Here, we have determined the solution structure of the, Myb domain of hRap1 by NMR. It contains three helices maintained by a, hydrophobic core. The architecture of the hRap1 Myb domain is very close, to that of each of the Myb domains from TRF1, scRap1p and c-Myb. However, the electrostatic potential surface of the hRap1 Myb domain is, distinguished from that of the other Myb domains. Each of the minimal, DNA-binding domains, containing one Myb domain in TRF1 and two Myb domains, in scRap1p and c-Myb, exhibits a positively charged broad surface that, contacts closely the negatively charged backbone of DNA. By contrast, the, hRap1 Myb domain shows no distinct positive surface, explaining its lack, of DNA-binding activity. The hRap1 Myb domain may be a member of a second, class of Myb motifs that lacks DNA-binding activity but may interact, instead with other proteins. Other possible members of this class are the, c-Myb R1 Myb domain and the Myb domains of ADA2 and Adf1. Thus, while the, folds of all Myb domains resemble each other closely, the function of each, Myb domain depends on the amino acid residues that are located on the, surface of each protein. | + | <StructureSection load='1fex' size='340' side='right'caption='[[1fex]]' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1fex]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FEX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1FEX FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1fex FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fex OCA], [https://pdbe.org/1fex PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1fex RCSB], [https://www.ebi.ac.uk/pdbsum/1fex PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1fex ProSAT], [https://www.topsan.org/Proteins/RSGI/1fex TOPSAN]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/TE2IP_HUMAN TE2IP_HUMAN] Acts both as a regulator of telomere function and as a transcription regulator. Involved in the regulation of telomere length and protection as a component of the shelterin complex (telosome). In contrast to other components of the shelterin complex, it is dispensible for telomere capping and does not participate in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair. Instead, it is required to negatively regulate telomere recombination and is essential for repressing homology-directed repair (HDR), which can affect telomere length. Does not bind DNA directly: recruited to telomeric double-stranded 5'-TTAGGG-3' repeats via its interaction with TERF2. Independently of its function in telomeres, also acts as a transcription regulator: recruited to extratelomeric 5'-TTAGGG-3' sites via its association with TERF2 or other factors, and regulates gene expression. When cytoplasmic, associates with the I-kappa-B-kinase (IKK) complex and acts as a regulator of the NF-kappa-B signaling by promoting IKK-mediated phosphorylation of RELA/p65, leading to activate expression of NF-kappa-B target genes.<ref>PMID:16166375</ref> <ref>PMID:19763083</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fe/1fex_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1fex ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Mammalian telomeres are composed of long tandem arrays of double-stranded telomeric TTAGGG repeats associated with the telomeric DNA-binding proteins, TRF1 and TRF2. TRF1 and TRF2 contain a similar C-terminal Myb domain that mediates sequence-specific binding to telomeric DNA. In the budding yeast, telomeric DNA is associated with scRap1p, which has a central DNA-binding domain that contains two structurally related Myb domains connected by a long linker, an N-terminal BRCT domain, and a C-terminal RCT domain. Recently, the human ortholog of scRap1p (hRap1) was identified and shown to contain a BRCT domain and an RCT domain similar to scRap1p. However, hRap1 contained only one recognizable Myb motif in the center of the protein. Furthermore, while scRap1p binds telomeric DNA directly, hRap1 has no DNA-binding ability. Instead, hRap1 is tethered to telomeres by TRF2. Here, we have determined the solution structure of the Myb domain of hRap1 by NMR. It contains three helices maintained by a hydrophobic core. The architecture of the hRap1 Myb domain is very close to that of each of the Myb domains from TRF1, scRap1p and c-Myb. However, the electrostatic potential surface of the hRap1 Myb domain is distinguished from that of the other Myb domains. Each of the minimal DNA-binding domains, containing one Myb domain in TRF1 and two Myb domains in scRap1p and c-Myb, exhibits a positively charged broad surface that contacts closely the negatively charged backbone of DNA. By contrast, the hRap1 Myb domain shows no distinct positive surface, explaining its lack of DNA-binding activity. The hRap1 Myb domain may be a member of a second class of Myb motifs that lacks DNA-binding activity but may interact instead with other proteins. Other possible members of this class are the c-Myb R1 Myb domain and the Myb domains of ADA2 and Adf1. Thus, while the folds of all Myb domains resemble each other closely, the function of each Myb domain depends on the amino acid residues that are located on the surface of each protein. |
| | | | |
| - | ==Disease==
| + | NMR structure of the hRap1 Myb motif reveals a canonical three-helix bundle lacking the positive surface charge typical of Myb DNA-binding domains.,Hanaoka S, Nagadoi A, Yoshimura S, Aimoto S, Li B, de Lange T, Nishimura Y J Mol Biol. 2001 Sep 7;312(1):167-75. PMID:11545594<ref>PMID:11545594</ref> |
| - | Known disease associated with this structure: Lymphocytic leukemia, acute T-cell OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=179502 179502]]
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 1FEX is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1FEX OCA].
| + | </div> |
| - | | + | <div class="pdbe-citations 1fex" style="background-color:#fffaf0;"></div> |
| - | ==Reference== | + | == References == |
| - | NMR structure of the hRap1 Myb motif reveals a canonical three-helix bundle lacking the positive surface charge typical of Myb DNA-binding domains., Hanaoka S, Nagadoi A, Yoshimura S, Aimoto S, Li B, de Lange T, Nishimura Y, J Mol Biol. 2001 Sep 7;312(1):167-75. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11545594 11545594]
| + | <references/> |
| - | [[Category: Single protein]]
| + | __TOC__ |
| - | [[Category: Hanaoka, S.]]
| + | </StructureSection> |
| - | [[Category: Nishimura, Y.]]
| + | [[Category: Homo sapiens]] |
| - | [[Category: RSGI, RIKEN.Structural.Genomics/Proteomics.Initiative.]]
| + | [[Category: Large Structures]] |
| - | [[Category: helix turn helix]] | + | [[Category: Hanaoka S]] |
| - | [[Category: riken structural genomics/proteomics initiative]] | + | [[Category: Nishimura Y]] |
| - | [[Category: rsgi]] | + | |
| - | [[Category: structural genomics]] | + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:52:34 2007''
| + | |
| Structural highlights
Function
TE2IP_HUMAN Acts both as a regulator of telomere function and as a transcription regulator. Involved in the regulation of telomere length and protection as a component of the shelterin complex (telosome). In contrast to other components of the shelterin complex, it is dispensible for telomere capping and does not participate in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair. Instead, it is required to negatively regulate telomere recombination and is essential for repressing homology-directed repair (HDR), which can affect telomere length. Does not bind DNA directly: recruited to telomeric double-stranded 5'-TTAGGG-3' repeats via its interaction with TERF2. Independently of its function in telomeres, also acts as a transcription regulator: recruited to extratelomeric 5'-TTAGGG-3' sites via its association with TERF2 or other factors, and regulates gene expression. When cytoplasmic, associates with the I-kappa-B-kinase (IKK) complex and acts as a regulator of the NF-kappa-B signaling by promoting IKK-mediated phosphorylation of RELA/p65, leading to activate expression of NF-kappa-B target genes.[1] [2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Mammalian telomeres are composed of long tandem arrays of double-stranded telomeric TTAGGG repeats associated with the telomeric DNA-binding proteins, TRF1 and TRF2. TRF1 and TRF2 contain a similar C-terminal Myb domain that mediates sequence-specific binding to telomeric DNA. In the budding yeast, telomeric DNA is associated with scRap1p, which has a central DNA-binding domain that contains two structurally related Myb domains connected by a long linker, an N-terminal BRCT domain, and a C-terminal RCT domain. Recently, the human ortholog of scRap1p (hRap1) was identified and shown to contain a BRCT domain and an RCT domain similar to scRap1p. However, hRap1 contained only one recognizable Myb motif in the center of the protein. Furthermore, while scRap1p binds telomeric DNA directly, hRap1 has no DNA-binding ability. Instead, hRap1 is tethered to telomeres by TRF2. Here, we have determined the solution structure of the Myb domain of hRap1 by NMR. It contains three helices maintained by a hydrophobic core. The architecture of the hRap1 Myb domain is very close to that of each of the Myb domains from TRF1, scRap1p and c-Myb. However, the electrostatic potential surface of the hRap1 Myb domain is distinguished from that of the other Myb domains. Each of the minimal DNA-binding domains, containing one Myb domain in TRF1 and two Myb domains in scRap1p and c-Myb, exhibits a positively charged broad surface that contacts closely the negatively charged backbone of DNA. By contrast, the hRap1 Myb domain shows no distinct positive surface, explaining its lack of DNA-binding activity. The hRap1 Myb domain may be a member of a second class of Myb motifs that lacks DNA-binding activity but may interact instead with other proteins. Other possible members of this class are the c-Myb R1 Myb domain and the Myb domains of ADA2 and Adf1. Thus, while the folds of all Myb domains resemble each other closely, the function of each Myb domain depends on the amino acid residues that are located on the surface of each protein.
NMR structure of the hRap1 Myb motif reveals a canonical three-helix bundle lacking the positive surface charge typical of Myb DNA-binding domains.,Hanaoka S, Nagadoi A, Yoshimura S, Aimoto S, Li B, de Lange T, Nishimura Y J Mol Biol. 2001 Sep 7;312(1):167-75. PMID:11545594[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ Sarthy J, Bae NS, Scrafford J, Baumann P. Human RAP1 inhibits non-homologous end joining at telomeres. EMBO J. 2009 Nov 4;28(21):3390-9. doi: 10.1038/emboj.2009.275. Epub 2009 Sep 17. PMID:19763083 doi:10.1038/emboj.2009.275
- ↑ Hanaoka S, Nagadoi A, Yoshimura S, Aimoto S, Li B, de Lange T, Nishimura Y. NMR structure of the hRap1 Myb motif reveals a canonical three-helix bundle lacking the positive surface charge typical of Myb DNA-binding domains. J Mol Biol. 2001 Sep 7;312(1):167-75. PMID:11545594 doi:10.1006/jmbi.2001.4924
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