4a0k

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STRUCTURE OF DDB1-DDB2-CUL4A-RBX1 BOUND TO A 12 BP ABASIC SITE CONTAINING DNA-DUPLEX

Structural highlights

4a0k is a 6 chain structure with sequence from Danio rerio, Homo sapiens, Mus musculus and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 5.93Å
Ligands:3DR
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.[1] [2] [3] [4] [5] [6]

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[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
78 reviews cite this structure
Induced protein degradation: an emerging drug discovery paradigm.
Lai et al. (2017)
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See Also

References

  1. ↑ Higa LA, Mihaylov IS, Banks DP, Zheng J, Zhang H. Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes constitutes a new checkpoint. Nat Cell Biol. 2003 Nov;5(11):1008-15. Epub 2003 Oct 26. PMID:14578910 doi:10.1038/ncb1061
  2. ↑ Zhang Y, Morrone G, Zhang J, Chen X, Lu X, Ma L, Moore M, Zhou P. CUL-4A stimulates ubiquitylation and degradation of the HOXA9 homeodomain protein. EMBO J. 2003 Nov 17;22(22):6057-67. PMID:14609952 doi:http://dx.doi.org/10.1093/emboj/cdg577
  3. ↑ Nag A, Bagchi S, Raychaudhuri P. Cul4A physically associates with MDM2 and participates in the proteolysis of p53. Cancer Res. 2004 Nov 15;64(22):8152-5. PMID:15548678 doi:http://dx.doi.org/10.1158/0008-5472.CAN-04-2598
  4. ↑ Hu J, McCall CM, Ohta T, Xiong Y. Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nat Cell Biol. 2004 Oct;6(10):1003-9. Epub 2004 Sep 26. PMID:15448697 doi:10.1038/ncb1172
  5. ↑ Wang H, Zhai L, Xu J, Joo HY, Jackson S, Erdjument-Bromage H, Tempst P, Xiong Y, Zhang Y. Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. Mol Cell. 2006 May 5;22(3):383-94. PMID:16678110 doi:S1097-2765(06)00230-9
  6. ↑ Bondar T, Kalinina A, Khair L, Kopanja D, Nag A, Bagchi S, Raychaudhuri P. Cul4A and DDB1 associate with Skp2 to target p27Kip1 for proteolysis involving the COP9 signalosome. Mol Cell Biol. 2006 Apr;26(7):2531-9. PMID:16537899 doi:http://dx.doi.org/26/7/2531
  7. ↑ 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

Contents


PDB ID 4a0k

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