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| - | ==STRUCTURE OF THE CAND1-CUL4B-RBX1 COMPLEX== | + | |
| - | <StructureSection load='4a0c' size='340' side='right' caption='[[4a0c]], [[Resolution|resolution]] 3.80Å' scene=''> | + | ==Structure of the CAND1-CUL4B-RBX1 complex== |
| | + | <StructureSection load='4a0c' size='340' side='right'caption='[[4a0c]], [[Resolution|resolution]] 3.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4a0c]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4A0C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A0C FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4a0c]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4A0C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4A0C FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1u6g|1u6g]], [[4a0l|4a0l]], [[4a0k|4a0k]]</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> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4a0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a0c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4a0c RCSB], [http://www.ebi.ac.uk/pdbsum/4a0c PDBsum]</span></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=4a0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a0c OCA], [https://pdbe.org/4a0c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4a0c RCSB], [https://www.ebi.ac.uk/pdbsum/4a0c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4a0c ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/CUL4B_HUMAN CUL4B_HUMAN]] Defects in CUL4B are the cause of mental retardation, X-linked, syndromic, 15 (MRXS15) [MIM:[http://omim.org/entry/300354 300354]]. A syndromic form of X-linked mental retardation characterized by severe intellectual deficit associated with short stature, craniofacial dysmorphism, small testes, muscle wasting in lower legs, kyphosis, joint hyperextensibility, pes cavus, small feet, and abnormalities of the toes. Additional neurologic manifestations include speech delay and impairment, tremor, seizures, gait ataxia, hyperactivity and decreased attention span.<ref>PMID:17273978</ref> <ref>PMID:20002452</ref> <ref>PMID:17236139</ref> <ref>PMID:19377476</ref> | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CAND1_HUMAN CAND1_HUMAN]] Enhances transcription from various types of promoters (By similarity). Regulatory protein that interferes with the assembly of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex and thereby down-regulates ubiquitination of target proteins. Prevents neddylation of CUL1 by physically blocking access to the neddylation site. Disrupts interactions between CUL1 and SKP1 and between CUL1 and F-box proteins.<ref>PMID:12504026</ref> <ref>PMID:12504025</ref> <ref>PMID:12609982</ref> [[http://www.uniprot.org/uniprot/CUL4B_HUMAN CUL4B_HUMAN]] Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition subunit. CUL4B may act within the complex as a scaffold protein, contributing to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. Plays a role as part of the E3 ubiquitin-protein ligase complex in polyubiquitination of CDT1, histone H2A, histone H3 and histone H4 in response to radiation-induced DNA damage. Targeted to UV damaged chromatin by DDB2 and may be important for DNA repair and DNA replication. Required for ubiquitination of cyclin E, and consequently, normal G1 cell cycle progression. Regulates the mammalian target-of-rapamycin (mTOR) pathway involved in control of cell growth, size and metabolism. Specific CUL4B regulation of the mTORC1-mediated pathway is dependent upon 26S proteasome function and requires interaction between CUL4B and MLST8.<ref>PMID:14578910</ref> <ref>PMID:16322693</ref> <ref>PMID:16678110</ref> <ref>PMID:18593899</ref> <ref>PMID:18235224</ref> <ref>PMID:19801544</ref> | + | [https://www.uniprot.org/uniprot/CAND1_HUMAN CAND1_HUMAN] Enhances transcription from various types of promoters (By similarity). Regulatory protein that interferes with the assembly of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex and thereby down-regulates ubiquitination of target proteins. Prevents neddylation of CUL1 by physically blocking access to the neddylation site. Disrupts interactions between CUL1 and SKP1 and between CUL1 and F-box proteins.<ref>PMID:12504026</ref> <ref>PMID:12504025</ref> <ref>PMID:12609982</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4a0c" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Ubiquitin protein ligase|Ubiquitin protein ligase]] | + | *[[Cullin 3D structures|Cullin 3D structures]] |
| | + | *[[Ring box protein 3D structures|Ring box protein 3D structures]] |
| | + | *[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Mus musculus]] | | [[Category: Mus musculus]] |
| - | [[Category: Faty, M]] | + | [[Category: Faty M]] |
| - | [[Category: Fischer, E S]] | + | [[Category: Fischer ES]] |
| - | [[Category: Gut, H]] | + | [[Category: Gut H]] |
| - | [[Category: Scrima, A]] | + | [[Category: Scrima A]] |
| - | [[Category: Thoma, N H]] | + | [[Category: Thoma NH]] |
| - | [[Category: Cell cycle]]
| + | |
| - | [[Category: Dna damage repair]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Ubiquitin]]
| + | |
| Structural highlights
Function
CAND1_HUMAN Enhances transcription from various types of promoters (By similarity). Regulatory protein that interferes with the assembly of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex and thereby down-regulates ubiquitination of target proteins. Prevents neddylation of CUL1 by physically blocking access to the neddylation site. Disrupts interactions between CUL1 and SKP1 and between CUL1 and F-box proteins.[1] [2] [3]
Publication Abstract from PubMed
The DDB1-CUL4-RBX1 (CRL4) ubiquitin ligase family regulates a diverse set of cellular pathways through dedicated substrate receptors (DCAFs). The DCAF DDB2 detects UV-induced pyrimidine dimers in the genome and facilitates nucleotide excision repair. We provide the molecular basis for DDB2 receptor-mediated cyclobutane pyrimidine dimer recognition in chromatin. The structures of the fully assembled DDB1-DDB2-CUL4A/B-RBX1 (CRL4(DDB2)) ligases reveal that the mobility of the ligase arm creates a defined ubiquitination zone around the damage, which precludes direct ligase activation by DNA lesions. Instead, the COP9 signalosome (CSN) mediates the CRL4(DDB2) inhibition in a CSN5 independent, nonenzymatic, fashion. In turn, CSN inhibition is relieved upon DNA damage binding to the DDB2 module within CSN-CRL4(DDB2). The Cockayne syndrome A DCAF complex crystal structure shows that CRL4(DCAF(WD40)) ligases share common architectural features. Our data support a general mechanism of ligase activation, which is induced by CSN displacement from CRL4(DCAF) on substrate binding to the DCAF.
The Molecular Basis of CRL4(DDB2/CSA) Ubiquitin Ligase Architecture, Targeting, and Activation.,Fischer ES, Scrima A, Bohm K, Matsumoto S, Lingaraju GM, Faty M, Yasuda T, Cavadini S, Wakasugi M, Hanaoka F, Iwai S, Gut H, Sugasawa K, Thoma NH Cell. 2011 Nov 23;147(5):1024-39. PMID:22118460[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zheng J, Yang X, Harrell JM, Ryzhikov S, Shim EH, Lykke-Andersen K, Wei N, Sun H, Kobayashi R, Zhang H. CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex. Mol Cell. 2002 Dec;10(6):1519-26. PMID:12504026
- ↑ Liu J, Furukawa M, Matsumoto T, Xiong Y. NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1-SKP1 binding and SCF ligases. Mol Cell. 2002 Dec;10(6):1511-8. PMID:12504025
- ↑ Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB. TIP120A associates with cullins and modulates ubiquitin ligase activity. J Biol Chem. 2003 May 2;278(18):15905-10. Epub 2003 Feb 27. PMID:12609982 doi:10.1074/jbc.M213070200
- ↑ Fischer ES, Scrima A, Bohm K, Matsumoto S, Lingaraju GM, Faty M, Yasuda T, Cavadini S, Wakasugi M, Hanaoka F, Iwai S, Gut H, Sugasawa K, Thoma NH. The Molecular Basis of CRL4(DDB2/CSA) Ubiquitin Ligase Architecture, Targeting, and Activation. Cell. 2011 Nov 23;147(5):1024-39. PMID:22118460 doi:10.1016/j.cell.2011.10.035
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