| Structural highlights
4z8l is a 6 chain structure with sequence from Civ, Human and Mansp. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | ZN |
| Gene: | VPRBP, DCAF1, KIAA0800, RIP (HUMAN), vpx (CIV), SAMHD1 (MANSP) |
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
Sterile Alpha Motif (SAM) and Histidine/Aspartate (HD) containing protein 1 (SAMHD1) restricts HIV/SIV infection in certain cell types and is counteracted by the virulence factor Vpx. Current evidence indicates that Vpx recruits SAMHD1 to the Cullin4-Ring Finger E3 ubiquitin ligase (CRL4) by facilitating an interaction between SAMHD1 and the substrate receptor DDB1- and Cullin4-associated factor 1 (DCAF1), thereby targeting SAMHD1 for proteasome-dependent down-regulation. Host-pathogen coevolution and positive selection at the interfaces of host-pathogen complexes are associated with sequence divergence and varying functional consequences. Two alternative interaction interfaces are used by SAMHD1 and Vpx: SamHD1's N-terminal tail and the adjacent SAM domain or the C-terminal tail proceeding the HD domain, are targeted by different Vpx variants in a unique fashion. In contrast, the C-terminal WD40 domain of DCAF1 interfaces similarly with the two above complexes. Comprehensive biochemical and structural biology approaches permitted us to delineate details of clade-specific recognition of SAMHD1 by lentiviral Vpx proteins. We show that not only the SAM domain but also the N-terminal tail engages in the DCAF1-Vpx interaction. Further, we show that changing the single Ser52 in human SAMHD1 to Phe, the residue found in SAMHD1 of Red-capped monkey (RCM) and Mandril (MND), allows it to be recognized by Vpx proteins of simian viruses infecting those primate species, which normally does not target wild type human SAMHD1 for degradation.
Structural basis of clade-specific engagement of SAMHD1 restriction factors by lentiviral Vpx virulence factors.,Wu Y, Koharudin LM, Mehrens J, DeLucia M, Byeon CH, Byeon IJ, Calero G, Ahn J, Gronenborn AM J Biol Chem. 2015 Jun 4. pii: jbc.M115.665513. PMID:26045556[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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:https://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:https://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:https://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:https://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:https://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:https://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:https://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:https://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:https://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:https://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:https://dx.doi.org/10.1016/j.molcel.2012.09.004
- ↑ Wu Y, Koharudin LM, Mehrens J, DeLucia M, Byeon CH, Byeon IJ, Calero G, Ahn J, Gronenborn AM. Structural basis of clade-specific engagement of SAMHD1 restriction factors by lentiviral Vpx virulence factors. J Biol Chem. 2015 Jun 4. pii: jbc.M115.665513. PMID:26045556 doi:https://dx.doi.org/10.1074/jbc.M115.665513
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