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| - | [[Image:2phe.gif|left|200px]]<br /> | |
| - | <applet load="2phe" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2phe" /> | |
| - | '''Model for VP16 binding to PC4'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Model for VP16 binding to PC4== |
| - | Herpes simplex virion protein 16 (VP16) contains two strong activation, regions that can independently and cooperatively activate transcription in, vivo. We have identified the regions and residues involved in the, interaction with the human transcriptional coactivator positive cofactor 4, (PC4) and the general transcription factor TFIIB. NMR and biochemical, experiments revealed that both VP16 activation regions are required for, the interaction and undergo a conformational transition from random coil, to alpha-helix upon binding to its target PC4. The interaction is strongly, electrostatically driven and the binding to PC4 is enhanced by the, presence of its amino-terminal domain. We propose models for binding of, VP16 to the core domains of PC4 and TFIIB that are based on two, independent docking approaches using NMR chemical shift changes observed, in titration experiments. The models are consistent with results from, site-directed mutagenesis and provide an explanation for the contribution, of both acidic and hydrophobic residues for transcriptional activation by, VP16. Both intrinsically unstructured activation domains are attracted to, their interaction partner by electrostatic interactions, and adopt an, alpha-helical conformation around the important hydrophobic residues. The, models showed multiple distinct binding surfaces upon interaction with, various partners, providing an explanation for the promiscuous properties, cooperativity, and the high activity of this activation domain. | + | <StructureSection load='2phe' size='340' side='right'caption='[[2phe]]' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2phe]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_alphaherpesvirus_1_strain_17 Human alphaherpesvirus 1 strain 17]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PHE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2PHE 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=2phe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2phe OCA], [https://pdbe.org/2phe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2phe RCSB], [https://www.ebi.ac.uk/pdbsum/2phe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2phe ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/TCP4_HUMAN TCP4_HUMAN] General coactivator that functions cooperatively with TAFs and mediates functional interactions between upstream activators and the general transcriptional machinery. May be involved in stabilizing the multiprotein transcription complex. Binds single-stranded DNA. Also binds, in vitro, non-specifically to double-stranded DNA (ds DNA).<ref>PMID:8062392</ref> <ref>PMID:8062391</ref> <ref>PMID:7628453</ref> <ref>PMID:9482861</ref> <ref>PMID:16689930</ref> <ref>PMID:9360603</ref> <ref>PMID:16605275</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/ph/2phe_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=2phe ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Herpes simplex virion protein 16 (VP16) contains two strong activation regions that can independently and cooperatively activate transcription in vivo. We have identified the regions and residues involved in the interaction with the human transcriptional coactivator positive cofactor 4 (PC4) and the general transcription factor TFIIB. NMR and biochemical experiments revealed that both VP16 activation regions are required for the interaction and undergo a conformational transition from random coil to alpha-helix upon binding to its target PC4. The interaction is strongly electrostatically driven and the binding to PC4 is enhanced by the presence of its amino-terminal domain. We propose models for binding of VP16 to the core domains of PC4 and TFIIB that are based on two independent docking approaches using NMR chemical shift changes observed in titration experiments. The models are consistent with results from site-directed mutagenesis and provide an explanation for the contribution of both acidic and hydrophobic residues for transcriptional activation by VP16. Both intrinsically unstructured activation domains are attracted to their interaction partner by electrostatic interactions, and adopt an alpha-helical conformation around the important hydrophobic residues. The models showed multiple distinct binding surfaces upon interaction with various partners, providing an explanation for the promiscuous properties, cooperativity, and the high activity of this activation domain. |
| | | | |
| - | ==About this Structure==
| + | Structural properties of the promiscuous VP16 activation domain.,Jonker HR, Wechselberger RW, Boelens R, Folkers GE, Kaptein R Biochemistry. 2005 Jan 25;44(3):827-39. PMID:15654739<ref>PMID:15654739</ref> |
| - | 2PHE is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Human_herpesvirus_4 Human herpesvirus 4]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2PHE OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Structural properties of the promiscuous VP16 activation domain., Jonker HR, Wechselberger RW, Boelens R, Folkers GE, Kaptein R, Biochemistry. 2005 Jan 25;44(3):827-39. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15654739 15654739]
| + | </div> |
| | + | <div class="pdbe-citations 2phe" style="background-color:#fffaf0;"></div> |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Human herpesvirus 4]] | + | [[Category: Human alphaherpesvirus 1 strain 17]] |
| - | [[Category: Protein complex]] | + | [[Category: Large Structures]] |
| - | [[Category: Boelens, R.]] | + | [[Category: Boelens R]] |
| - | [[Category: Folkers, G.E.]] | + | [[Category: Folkers GE]] |
| - | [[Category: Jonker, H.R.A.]] | + | [[Category: Jonker HRA]] |
| - | [[Category: Kaptein, R.]] | + | [[Category: Kaptein R]] |
| - | [[Category: Wechselberger, R.W.]] | + | [[Category: Wechselberger RW]] |
| - | [[Category: activator]]
| + | |
| - | [[Category: cofactor]]
| + | |
| - | [[Category: pc4]]
| + | |
| - | [[Category: transcription]]
| + | |
| - | [[Category: vp16]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:23:54 2007''
| + | |
| Structural highlights
Function
TCP4_HUMAN General coactivator that functions cooperatively with TAFs and mediates functional interactions between upstream activators and the general transcriptional machinery. May be involved in stabilizing the multiprotein transcription complex. Binds single-stranded DNA. Also binds, in vitro, non-specifically to double-stranded DNA (ds DNA).[1] [2] [3] [4] [5] [6] [7]
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
Herpes simplex virion protein 16 (VP16) contains two strong activation regions that can independently and cooperatively activate transcription in vivo. We have identified the regions and residues involved in the interaction with the human transcriptional coactivator positive cofactor 4 (PC4) and the general transcription factor TFIIB. NMR and biochemical experiments revealed that both VP16 activation regions are required for the interaction and undergo a conformational transition from random coil to alpha-helix upon binding to its target PC4. The interaction is strongly electrostatically driven and the binding to PC4 is enhanced by the presence of its amino-terminal domain. We propose models for binding of VP16 to the core domains of PC4 and TFIIB that are based on two independent docking approaches using NMR chemical shift changes observed in titration experiments. The models are consistent with results from site-directed mutagenesis and provide an explanation for the contribution of both acidic and hydrophobic residues for transcriptional activation by VP16. Both intrinsically unstructured activation domains are attracted to their interaction partner by electrostatic interactions, and adopt an alpha-helical conformation around the important hydrophobic residues. The models showed multiple distinct binding surfaces upon interaction with various partners, providing an explanation for the promiscuous properties, cooperativity, and the high activity of this activation domain.
Structural properties of the promiscuous VP16 activation domain.,Jonker HR, Wechselberger RW, Boelens R, Folkers GE, Kaptein R Biochemistry. 2005 Jan 25;44(3):827-39. PMID:15654739[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kretzschmar M, Kaiser K, Lottspeich F, Meisterernst M. A novel mediator of class II gene transcription with homology to viral immediate-early transcriptional regulators. Cell. 1994 Aug 12;78(3):525-34. PMID:8062392
- ↑ Ge H, Roeder RG. Purification, cloning, and characterization of a human coactivator, PC4, that mediates transcriptional activation of class II genes. Cell. 1994 Aug 12;78(3):513-23. PMID:8062391
- ↑ Kaiser K, Stelzer G, Meisterernst M. The coactivator p15 (PC4) initiates transcriptional activation during TFIIA-TFIID-promoter complex formation. EMBO J. 1995 Jul 17;14(14):3520-7. PMID:7628453
- ↑ Malik S, Guermah M, Roeder RG. A dynamic model for PC4 coactivator function in RNA polymerase II transcription. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2192-7. PMID:9482861
- ↑ Jonker HR, Wechselberger RW, Pinkse M, Kaptein R, Folkers GE. Gradual phosphorylation regulates PC4 coactivator function. FEBS J. 2006 Apr;273(7):1430-44. PMID:16689930 doi:http://dx.doi.org/10.1111/j.1742-4658.2006.05165.x
- ↑ Brandsen J, Werten S, van der Vliet PC, Meisterernst M, Kroon J, Gros P. C-terminal domain of transcription cofactor PC4 reveals dimeric ssDNA binding site. Nat Struct Biol. 1997 Nov;4(11):900-3. PMID:9360603
- ↑ Jonker HR, Wechselberger RW, Boelens R, Kaptein R, Folkers GE. The intrinsically unstructured domain of PC4 modulates the activity of the structured core through inter- and intramolecular interactions. Biochemistry. 2006 Apr 18;45(15):5067-81. PMID:16605275 doi:http://dx.doi.org/10.1021/bi052531b
- ↑ Jonker HR, Wechselberger RW, Boelens R, Folkers GE, Kaptein R. Structural properties of the promiscuous VP16 activation domain. Biochemistry. 2005 Jan 25;44(3):827-39. PMID:15654739 doi:10.1021/bi0482912
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