View source for 4z8l


==Crystal structure of DCAF1/SIV-MND VPX/MND SAMHD1 NTD ternary complex==
<StructureSection load='4z8l' size='340' side='right'caption='[[4z8l]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4z8l]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Mandrillus_sphinx Mandrillus sphinx] and [https://en.wikipedia.org/wiki/Simian_immunodeficiency_virus Simian immunodeficiency virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Z8L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Z8L FirstGlance]. <br>
</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'>[https://proteopedia.org/fgij/fg.htm?mol=4z8l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z8l OCA], [https://pdbe.org/4z8l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4z8l RCSB], [https://www.ebi.ac.uk/pdbsum/4z8l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4z8l ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DCAF1_HUMAN 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).<ref>PMID:16964240</ref> <ref>PMID:17609381</ref> <ref>PMID:17630831</ref> <ref>PMID:18332868</ref> <ref>PMID:18524771</ref> <ref>PMID:18606781</ref> <ref>PMID:19287380</ref> <ref>PMID:20644714</ref> <ref>PMID:22184063</ref> <ref>PMID:23063525</ref> <ref>PMID:23362280</ref> <ref>PMID:24140421</ref>   (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.<ref>PMID:17314515</ref> <ref>PMID:17559673</ref> <ref>PMID:17609381</ref> <ref>PMID:17620334</ref> <ref>PMID:17626091</ref> <ref>PMID:17630831</ref> <ref>PMID:18524771</ref> <ref>PMID:24116224</ref>   (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.<ref>PMID:17314515</ref> <ref>PMID:18464893</ref> <ref>PMID:19264781</ref> <ref>PMID:19923175</ref> <ref>PMID:24336198</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:26045556</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4z8l" style="background-color:#fffaf0;"></div>

==See Also==
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
*[[VprBP|VprBP]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mandrillus sphinx]]
[[Category: Simian immunodeficiency virus]]
[[Category: Ahn J]]
[[Category: Calero G]]
[[Category: Gronenborn AM]]
[[Category: Koharudin LM]]
[[Category: Wu Y]]