9y76

Structural highlights

Function

DCAF1_HUMAN Acts both as a substrate recognition component of E3 ubiquitin-protein ligase complexes and as an atypical serine/threonine-protein kinase, playing key roles in various processes such as cell cycle, telomerase regulation and histone modification. Probable substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, named CUL4A-RBX1-DDB1-DCAF1/VPRBP complex, which mediates ubiquitination and proteasome-dependent degradation of proteins such as NF2. Involved in the turnover of methylated proteins: recognizes and binds methylated proteins via its chromo domain, leading to ubiquitination of target proteins by the RBX1-DDB1-DCAF1/VPRBP complex (PubMed:23063525). The CUL4A-RBX1-DDB1-DCAF1/VPRBP complex is also involved in B-cell development: DCAF1 is recruited by RAG1 to ubiquitinate proteins, leading to limit error-prone repair during V(D)J recombination. Also part of the EDVP complex, an E3 ligase complex that mediates ubiquitination of proteins such as TERT, leading to TERT degradation and telomerase inhibition (PubMed:23362280). Also acts as an atypical serine/threonine-protein kinase that specifically mediates phosphorylation of 'Thr-120' of histone H2A (H2AT120ph) in a nucleosomal context, thereby repressing transcription. H2AT120ph is present in the regulatory region of many tumor suppresor genes, down-regulates their transcription and is present at high level in a number of tumors (PubMed:24140421). Involved in JNK-mediated apoptosis during cell competition process via its interaction with LLGL1 and LLGL2 (PubMed:20644714).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]} (Microbial infection) In case of infection by HIV-1 virus, it is recruited by HIV-1 Vpr in order to hijack the CUL4A-RBX1-DDB1-DCAF1/VPRBP function leading to arrest the cell cycle in G2 phase, and also to protect the viral protein from proteasomal degradation by another E3 ubiquitin ligase. The HIV-1 Vpr protein hijacks the CUL4A-RBX1-DDB1-DCAF1/VPRBP complex to promote ubiquitination and degradation of proteins such as TERT and ZIP/ZGPAT.^{[13] [14] [15] [16] [17] [18] [19] [20]} (Microbial infection) In case of infection by HIV-2 virus, it is recruited by HIV-2 Vpx in order to hijack the CUL4A-RBX1-DDB1-DCAF1/VPRBP function leading to enhanced efficiency of macrophage infection and promotion of the replication of cognate primate lentiviruses in cells of monocyte/macrophage lineage.^{[21] [22] [23] [24] [25]}

References

1. ↑ Angers S, Li T, Yi X, MacCoss MJ, Moon RT, Zheng N. Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature. 2006 Oct 5;443(7111):590-3. PMID:16964240 doi:10.1038/nature05175
2. ↑ Hrecka K, Gierszewska M, Srivastava S, Kozaczkiewicz L, Swanson SK, Florens L, Washburn MP, Skowronski J. Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle. Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11778-83. Epub 2007 Jul 3. PMID:17609381 doi:http://dx.doi.org/10.1073/pnas.0702102104
3. ↑ Belzile JP, Duisit G, Rougeau N, Mercier J, Finzi A, Cohen EA. HIV-1 Vpr-mediated G2 arrest involves the DDB1-CUL4AVPRBP E3 ubiquitin ligase. PLoS Pathog. 2007 Jul;3(7):e85. PMID:17630831 doi:http://dx.doi.org/10.1371/journal.ppat.0030085
4. ↑ Huang J, Chen J. VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. Oncogene. 2008 Jul 3;27(29):4056-64. Epub 2008 Mar 10. PMID:18332868 doi:onc200844
5. ↑ Le Rouzic E, Morel M, Ayinde D, Belaidouni N, Letienne J, Transy C, Margottin-Goguet F. Assembly with the Cul4A-DDB1DCAF1 ubiquitin ligase protects HIV-1 Vpr from proteasomal degradation. J Biol Chem. 2008 Aug 1;283(31):21686-92. doi: 10.1074/jbc.M710298200. Epub 2008 , Jun 4. PMID:18524771 doi:http://dx.doi.org/10.1074/jbc.M710298200
6. ↑ McCall CM, Miliani de Marval PL, Chastain PD 2nd, Jackson SC, He YJ, Kotake Y, Cook JG, Xiong Y. Human immunodeficiency virus type 1 Vpr-binding protein VprBP, a WD40 protein associated with the DDB1-CUL4 E3 ubiquitin ligase, is essential for DNA replication and embryonic development. Mol Cell Biol. 2008 Sep;28(18):5621-33. doi: 10.1128/MCB.00232-08. Epub 2008 Jul , 7. PMID:18606781 doi:http://dx.doi.org/10.1128/MCB.00232-08
7. ↑ Maddika S, Chen J. Protein kinase DYRK2 is a scaffold that facilitates assembly of an E3 ligase. Nat Cell Biol. 2009 Apr;11(4):409-19. doi: 10.1038/ncb1848. Epub 2009 Mar 15. PMID:19287380 doi:10.1038/ncb1848
8. ↑ Tamori Y, Bialucha CU, Tian AG, Kajita M, Huang YC, Norman M, Harrison N, Poulton J, Ivanovitch K, Disch L, Liu T, Deng WM, Fujita Y. Involvement of Lgl and Mahjong/VprBP in cell competition. PLoS Biol. 2010 Jul 13;8(7):e1000422. doi: 10.1371/journal.pbio.1000422. PMID:20644714 doi:http://dx.doi.org/10.1371/journal.pbio.1000422
9. ↑ Kim K, Heo K, Choi J, Jackson S, Kim H, Xiong Y, An W. Vpr-binding protein antagonizes p53-mediated transcription via direct interaction with H3 tail. Mol Cell Biol. 2012 Feb;32(4):783-96. doi: 10.1128/MCB.06037-11. Epub 2011 Dec, 19. PMID:22184063 doi:http://dx.doi.org/10.1128/MCB.06037-11
10. ↑ Lee JM, Lee JS, Kim H, Kim K, Park H, Kim JY, Lee SH, Kim IS, Kim J, Lee M, Chung CH, Seo SB, Yoon JB, Ko E, Noh DY, Kim KI, Kim KK, Baek SH. EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol Cell. 2012 Nov 30;48(4):572-86. doi: 10.1016/j.molcel.2012.09.004. Epub 2012 , Oct 11. PMID:23063525 doi:http://dx.doi.org/10.1016/j.molcel.2012.09.004
11. ↑ Jung HY, Wang X, Jun S, Park JI. Dyrk2-associated EDD-DDB1-VprBP E3 ligase inhibits telomerase by TERT degradation. J Biol Chem. 2013 Mar 8;288(10):7252-62. doi: 10.1074/jbc.M112.416792. Epub 2013 , Jan 28. PMID:23362280 doi:http://dx.doi.org/10.1074/jbc.M112.416792
12. ↑ Kim K, Kim JM, Kim JS, Choi J, Lee YS, Neamati N, Song JS, Heo K, An W. VprBP has intrinsic kinase activity targeting histone H2A and represses gene transcription. Mol Cell. 2013 Nov 7;52(3):459-67. doi: 10.1016/j.molcel.2013.09.017. Epub 2013, Oct 17. PMID:24140421 doi:http://dx.doi.org/10.1016/j.molcel.2013.09.017
13. ↑ Le Rouzic E, Belaidouni N, Estrabaud E, Morel M, Rain JC, Transy C, Margottin-Goguet F. HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase. Cell Cycle. 2007 Jan 15;6(2):182-8. Epub 2007 Jan 17. PMID:17314515
14. ↑ DeHart JL, Zimmerman ES, Ardon O, Monteiro-Filho CM, Arganaraz ER, Planelles V. HIV-1 Vpr activates the G2 checkpoint through manipulation of the ubiquitin proteasome system. Virol J. 2007 Jun 8;4:57. PMID:17559673 doi:http://dx.doi.org/10.1186/1743-422X-4-57
15. ↑ Hrecka K, Gierszewska M, Srivastava S, Kozaczkiewicz L, Swanson SK, Florens L, Washburn MP, Skowronski J. Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle. Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11778-83. Epub 2007 Jul 3. PMID:17609381 doi:http://dx.doi.org/10.1073/pnas.0702102104
16. ↑ Wen X, Duus KM, Friedrich TD, de Noronha CM. The HIV1 protein Vpr acts to promote G2 cell cycle arrest by engaging a DDB1 and Cullin4A-containing ubiquitin ligase complex using VprBP/DCAF1 as an adaptor. J Biol Chem. 2007 Sep 14;282(37):27046-57. Epub 2007 Jul 9. PMID:17620334 doi:http://dx.doi.org/10.1074/jbc.M703955200
17. ↑ Tan L, Ehrlich E, Yu XF. DDB1 and Cul4A are required for human immunodeficiency virus type 1 Vpr-induced G2 arrest. J Virol. 2007 Oct;81(19):10822-30. Epub 2007 Jul 11. PMID:17626091 doi:http://dx.doi.org/10.1128/JVI.01380-07
18. ↑ Belzile JP, Duisit G, Rougeau N, Mercier J, Finzi A, Cohen EA. HIV-1 Vpr-mediated G2 arrest involves the DDB1-CUL4AVPRBP E3 ubiquitin ligase. PLoS Pathog. 2007 Jul;3(7):e85. PMID:17630831 doi:http://dx.doi.org/10.1371/journal.ppat.0030085
19. ↑ Le Rouzic E, Morel M, Ayinde D, Belaidouni N, Letienne J, Transy C, Margottin-Goguet F. Assembly with the Cul4A-DDB1DCAF1 ubiquitin ligase protects HIV-1 Vpr from proteasomal degradation. J Biol Chem. 2008 Aug 1;283(31):21686-92. doi: 10.1074/jbc.M710298200. Epub 2008 , Jun 4. PMID:18524771 doi:http://dx.doi.org/10.1074/jbc.M710298200
20. ↑ Maudet C, Sourisce A, Dragin L, Lahouassa H, Rain JC, Bouaziz S, Ramirez BC, Margottin-Goguet F. HIV-1 Vpr induces the degradation of ZIP and sZIP, adaptors of the NuRD chromatin remodeling complex, by hijacking DCAF1/VprBP. PLoS One. 2013 Oct 8;8(10):e77320. doi: 10.1371/journal.pone.0077320. eCollection, 2013. PMID:24116224 doi:http://dx.doi.org/10.1371/journal.pone.0077320
21. ↑ Le Rouzic E, Belaidouni N, Estrabaud E, Morel M, Rain JC, Transy C, Margottin-Goguet F. HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase. Cell Cycle. 2007 Jan 15;6(2):182-8. Epub 2007 Jan 17. PMID:17314515
22. ↑ Srivastava S, Swanson SK, Manel N, Florens L, Washburn MP, Skowronski J. Lentiviral Vpx accessory factor targets VprBP/DCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligase to enable macrophage infection. PLoS Pathog. 2008 May 9;4(5):e1000059. doi: 10.1371/journal.ppat.1000059. PMID:18464893 doi:http://dx.doi.org/10.1371/journal.ppat.1000059
23. ↑ Bergamaschi A, Ayinde D, David A, Le Rouzic E, Morel M, Collin G, Descamps D, Damond F, Brun-Vezinet F, Nisole S, Margottin-Goguet F, Pancino G, Transy C. The human immunodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1 DCAF1 ubiquitin ligase to overcome a postentry block in macrophage infection. J Virol. 2009 May;83(10):4854-60. doi: 10.1128/JVI.00187-09. Epub 2009 Mar 4. PMID:19264781 doi:http://dx.doi.org/10.1128/JVI.00187-09
24. ↑ Gramberg T, Sunseri N, Landau NR. Evidence for an activation domain at the amino terminus of simian immunodeficiency virus Vpx. J Virol. 2010 Feb;84(3):1387-96. doi: 10.1128/JVI.01437-09. Epub 2009 Nov 18. PMID:19923175 doi:http://dx.doi.org/10.1128/JVI.01437-09
25. ↑ Schwefel D, Groom HC, Boucherit VC, Christodoulou E, Walker PA, Stoye JP, Bishop KN, Taylor IA. Structural basis of lentiviral subversion of a cellular protein degradation pathway. Nature. 2013 Dec 15. doi: 10.1038/nature12815. PMID:24336198 doi:http://dx.doi.org/10.1038/nature12815