| Structural highlights
Function
[MERL_MOUSE] Probable regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in tumor suppression by restricting proliferation and promoting apoptosis. Along with WWC1 can synergistically induce the phosphorylation of LATS1 and LATS2 and can probably function in the regulation of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway. May act as a membrane stabilizing protein. May inhibit PI3 kinase by binding to AGAP2 and impairing its stimulating activity. Suppresses cell proliferation and tumorigenesis by inhibiting the CUL4A-RBX1-DDB1-VprBP/DCAF1 E3 ubiquitin-protein ligase complex (By similarity). Plays a role in lens development and is required for complete fiber cell terminal differentiation, maintenance of cell polarity and separation of the lens vesicle from the corneal epithelium.[1] [VPRBP_HUMAN] Component of the CUL4A-RBX1-DDB1-VprBP/DCAF1 E3 ubiquitin-protein ligase complex, VprBP/DCAF1 may function as the substrate recognition module within this complex. For example, VprBP/DCAF1 targets NF2 to the E3 ubiquitin-ligase complex for ubiquitination and subsequent proteasome-dependent degradation. In case of infection by HIV-1 virus, it is recruited by HIV-1 Vpr in order to hijack the CUL4A-RBX1-DDB1 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. In case of infection by HIV-2 virus, it is recruited by HIV-2 Vpx in order to hijack the CUL4A-RBX1-DDB1 function leading to enhanced efficiency of macrophage infection and promotion of the replication of cognate primate lentiviruses in cells of monocyte/macrophage lineage. Associated with chromatin in a DDB1-independent and cell cycle-dependent manner, VprBP/DCAF1 is recruited to chromatin as DNA is being replicated and is released from chromatin before mitosis.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
Publication Abstract from PubMed
Merlin, a tumor suppressor encoded by the neurofibromatosis type 2 gene, has been shown to suppress tumorigenesis by inhibiting the Cullin 4-RING E3 ubiquitin ligase CRL4DCAF 1 in the nucleus. This inhibition is mediated by direct binding of merlin to DDB1-and-Cullin 4-associated Factor 1 (DCAF1), yet the binding mode of merlin to DCAF1 is not well defined. Here, we report structural and biophysical studies of the merlin binding to DCAF1 and its interference with CD44 binding. The crystal structure of the merlin FERM domain bound to the DCAF1 C-terminal acidic tail reveals that the hydrophobic IILXLN motif located at the C-terminal end of DCAF1 binds subdomain C of the FERM domain by forming a beta-strand. The binding site and mode resemble that of merlin binding to the CD44 cytoplasmic tail. Competition binding assay showed that CD44 and DCAF1 compete for binding to the merlin FERM domain in solution. The CD44 cytoplasmic tail is known to be cleaved for nuclear translocation by regulated intra-membrane proteolysis (RIP). Our structure implies that, in the nucleus, the CD44 cytoplasmic tail cleaved by RIP could release DCAF1 from merlin by competing for binding to the merlin FERM domain, which results in the inhibition of merlin-mediated suppression of tumorigenesis.
Structural basis of DDB1-and-Cullin 4-associated Factor 1 (DCAF1) recognition by merlin/NF2 and its implication in tumorigenesis by CD44-mediated inhibition of merlin suppression of DCAF1 function.,Mori T, Gotoh S, Shirakawa M, Hakoshima T Genes Cells. 2014 Jun 9. doi: 10.1111/gtc.12161. PMID:24912773[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wiley LA, Dattilo LK, Kang KB, Giovannini M, Beebe DC. The tumor suppressor merlin is required for cell cycle exit, terminal differentiation, and cell polarity in the developing murine lens. Invest Ophthalmol Vis Sci. 2010 Jul;51(7):3611-8. doi: 10.1167/iovs.09-4371. Epub, 2010 Feb 24. PMID:20181838 doi:http://dx.doi.org/10.1167/iovs.09-4371
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Mori T, Gotoh S, Shirakawa M, Hakoshima T. Structural basis of DDB1-and-Cullin 4-associated Factor 1 (DCAF1) recognition by merlin/NF2 and its implication in tumorigenesis by CD44-mediated inhibition of merlin suppression of DCAF1 function. Genes Cells. 2014 Jun 9. doi: 10.1111/gtc.12161. PMID:24912773 doi:http://dx.doi.org/10.1111/gtc.12161
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