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2hye

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(New page: 200px<br /> <applet load="2hye" size="450" color="white" frame="true" align="right" spinBox="true" caption="2hye, resolution 3.1&Aring;" /> '''Crystal Structure of...)
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[[Image:2hye.gif|left|200px]]<br />
 
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<applet load="2hye" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2hye, resolution 3.1&Aring;" />
 
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'''Crystal Structure of the DDB1-Cul4A-Rbx1-SV5V Complex'''<br />
 
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==Overview==
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==Crystal Structure of the DDB1-Cul4A-Rbx1-SV5V Complex==
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Protein ubiquitination is a common form of post-translational modification, that regulates a broad spectrum of protein substrates in diverse cellular, pathways. Through a three-enzyme (E1-E2-E3) cascade, the attachment of, ubiquitin to proteins is catalysed by the E3 ubiquitin ligase, which is, best represented by the superfamily of the cullin-RING complexes., Conserved from yeast to human, the DDB1-CUL4-ROC1 complex is a recently, identified cullin-RING ubiquitin ligase, which regulates DNA repair, DNA, replication and transcription, and can also be subverted by pathogenic, viruses to benefit viral infection. Lacking a canonical SKP1-like cullin, adaptor and a defined substrate recruitment module, how the DDB1-CUL4-ROC1, E3 apparatus is assembled for ubiquitinating various substrates remains, unclear. Here we present crystallographic analyses of the virally hijacked, form of the human DDB1-CUL4A-ROC1 machinery, which show that DDB1 uses one, beta-propeller domain for cullin scaffold binding and a variably attached, separate double-beta-propeller fold for substrate presentation. Through, tandem-affinity purification of human DDB1 and CUL4A complexes followed by, mass spectrometry analysis, we then identify a novel family of WD40-repeat, proteins, which directly bind to the double-propeller fold of DDB1 and, serve as the substrate-recruiting module of the E3. Together, our, structural and proteomic results reveal the structural mechanisms and, molecular logic underlying the assembly and versatility of a new family of, cullin-RING E3 complexes.
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<StructureSection load='2hye' size='340' side='right'caption='[[2hye]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2hye]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human] and [https://en.wikipedia.org/wiki/Parainfluenza_virus_5 Parainfluenza virus 5]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HYE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HYE FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DDB1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), P/V ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11207 Parainfluenza virus 5]), CUL4A ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), RBX1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2hye FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hye OCA], [https://pdbe.org/2hye PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2hye RCSB], [https://www.ebi.ac.uk/pdbsum/2hye PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2hye ProSAT]</span></td></tr>
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</table>
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== Function ==
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[[https://www.uniprot.org/uniprot/RBX1_HUMAN RBX1_HUMAN]] E3 ubiquitin ligase component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins, including proteins involved in cell cycle progression, signal transduction, transcription and transcription-coupled nucleotide excision repair. The functional specificity of the E3 ubiquitin-protein ligase complexes depends on the variable substrate recognition components. As a component of the CSA complex promotes the ubiquitination of ERCC6 resulting in proteasomal degradation. Through the RING-type zinc finger, seems to recruit the E2 ubiquitination enzyme, like CDC34, to the complex and brings it into close proximity to the substrate. Probably also stimulates CDC34 autoubiquitination. May be required for histone H3 and histone H4 ubiquitination in response to ultraviolet and for subsequent DNA repair. Promotes the neddylation of CUL1, CUL2, CUL4 and CUL4 via its interaction with UBE2M.<ref>PMID:10579999</ref> <ref>PMID:11027288</ref> <ref>PMID:16751180</ref> <ref>PMID:16678110</ref> <ref>PMID:19679664</ref> [[https://www.uniprot.org/uniprot/DDB1_HUMAN DDB1_HUMAN]] Required for DNA repair. Binds to DDB2 to form the UV-damaged DNA-binding protein complex (the UV-DDB complex). The UV-DDB complex may recognize UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair. The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches. Also appears to function as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the DCX E3 ubiquitin-protein ligase complex is determined by the variable substrate recognition component recruited by DDB1. DCX(DDB2) (also known as DDB1-CUL4-ROC1, CUL4-DDB-ROC1 and CUL4-DDB-RBX1) may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage. The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair. DCX(DDB2) also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication. DCX(ERCC8) (the CSA complex) plays a role in transcription-coupled repair (TCR). May also play a role in ubiquitination of CDKN1B/p27kip when associated with CUL4 and SKP2.<ref>PMID:12732143</ref> <ref>PMID:15448697</ref> <ref>PMID:14739464</ref> <ref>PMID:15882621</ref> <ref>PMID:16260596</ref> <ref>PMID:16482215</ref> <ref>PMID:17079684</ref> <ref>PMID:16407242</ref> <ref>PMID:16407252</ref> <ref>PMID:16678110</ref> <ref>PMID:16940174</ref> <ref>PMID:17041588</ref> <ref>PMID:16473935</ref> <ref>PMID:18593899</ref> <ref>PMID:18381890</ref> <ref>PMID:18332868</ref> [[https://www.uniprot.org/uniprot/CUL4A_HUMAN CUL4A_HUMAN]] Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component. DCX(DET1-COP1) directs ubiquitination of JUN. DCX(DDB2) directs ubiquitination of XPC. In association with RBX1, DDB1 and DDB2 is required for histone H3 and histone H4 ubiquitination in response to ultraviolet and may be important for subsequent DNA repair. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication. In association with DDB1 and SKP2 probably is involved in ubiquitination of CDKN1B/p27kip. Is involved in ubiquitination of HOXA9.<ref>PMID:14578910</ref> <ref>PMID:14609952</ref> <ref>PMID:15548678</ref> <ref>PMID:15448697</ref> <ref>PMID:16678110</ref> <ref>PMID:16537899</ref> [[https://www.uniprot.org/uniprot/V_SV5 V_SV5]] Blocks host interferon signaling. Induces the ubiquitination and subsequent proteasome-mediated degradation of host STAT1. Acts as an adapter, linking host DDB1-Cullin 4 to STAT2/STAT1 complex. There is an absolute requirement of STAT2 in STAT1 degradation, as V binds specifically to STAT2. Might act as a chaperone keeping the viral nucleoprotein soluble. Interacts with host IFIH1/MDA5 to block its activity in the transduction pathway which leads to the activation of IFN-beta promoter, thus protecting the virus against cell antiviral state.<ref>PMID:15950997</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hy/2hye_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=2hye ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Protein ubiquitination is a common form of post-translational modification that regulates a broad spectrum of protein substrates in diverse cellular pathways. Through a three-enzyme (E1-E2-E3) cascade, the attachment of ubiquitin to proteins is catalysed by the E3 ubiquitin ligase, which is best represented by the superfamily of the cullin-RING complexes. Conserved from yeast to human, the DDB1-CUL4-ROC1 complex is a recently identified cullin-RING ubiquitin ligase, which regulates DNA repair, DNA replication and transcription, and can also be subverted by pathogenic viruses to benefit viral infection. Lacking a canonical SKP1-like cullin adaptor and a defined substrate recruitment module, how the DDB1-CUL4-ROC1 E3 apparatus is assembled for ubiquitinating various substrates remains unclear. Here we present crystallographic analyses of the virally hijacked form of the human DDB1-CUL4A-ROC1 machinery, which show that DDB1 uses one beta-propeller domain for cullin scaffold binding and a variably attached separate double-beta-propeller fold for substrate presentation. Through tandem-affinity purification of human DDB1 and CUL4A complexes followed by mass spectrometry analysis, we then identify a novel family of WD40-repeat proteins, which directly bind to the double-propeller fold of DDB1 and serve as the substrate-recruiting module of the E3. Together, our structural and proteomic results reveal the structural mechanisms and molecular logic underlying the assembly and versatility of a new family of cullin-RING E3 complexes.
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==Disease==
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Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery.,Angers S, Li T, Yi X, MacCoss MJ, Moon RT, Zheng N Nature. 2006 Oct 5;443(7111):590-3. PMID:16964240<ref>PMID:16964240</ref>
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Known disease associated with this structure: Xeroderma pigmentosum, group E, subtype 2 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600045 600045]]
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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2HYE 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/Simian_virus_40 Simian virus 40] with ZN as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2HYE OCA].
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</div>
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<div class="pdbe-citations 2hye" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery., Angers S, Li T, Yi X, MacCoss MJ, Moon RT, Zheng N, Nature. 2006 Oct 5;443(7111):590-3. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16964240 16964240]
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*[[Cullin 3D structures|Cullin 3D structures]]
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[[Category: Homo sapiens]]
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*[[DNA damage-binding protein|DNA damage-binding protein]]
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[[Category: Protein complex]]
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*[[Nonstructural protein 3D structures|Nonstructural protein 3D structures]]
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[[Category: Simian virus 40]]
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*[[RING box protein|RING box protein]]
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[[Category: Angers, S.]]
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== References ==
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[[Category: Li, T.]]
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<references/>
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[[Category: MacCoss, M.J.]]
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__TOC__
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[[Category: Moon, R.T.]]
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</StructureSection>
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[[Category: Yi, X.]]
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[[Category: Human]]
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[[Category: Zheng, N.]]
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[[Category: Large Structures]]
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[[Category: ZN]]
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[[Category: Parainfluenza virus 5]]
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[[Category: beta propeller]]
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[[Category: Angers, S]]
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[[Category: cullin repeats]]
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[[Category: Li, T]]
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[[Category: helical repeats]]
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[[Category: MacCoss, M J]]
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[[Category: propeller cluster]]
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[[Category: Moon, R T]]
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[[Category: protein binding]]
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[[Category: Yi, X]]
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[[Category: ring finger]]
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[[Category: Zheng, N]]
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[[Category: zinc finger]]
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[[Category: Beta propeller]]
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[[Category: Cullin repeat]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:38:23 2007''
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[[Category: Helical repeat]]
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[[Category: Propeller cluster]]
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[[Category: Protein binding]]
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[[Category: Ring finger]]
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[[Category: Zinc finger]]

Current revision

Crystal Structure of the DDB1-Cul4A-Rbx1-SV5V Complex

PDB ID 2hye

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