4z8l

Crystal structure of DCAF1/SIV-MND VPX/MND SAMHD1 NTD ternary complex

spinqualitylabelsall models 4z8l, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4z8l is a 6 chain structure with sequence from Homo sapiens, Mandrillus sphinx and Simian immunodeficiency virus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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). (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. (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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine/threonine protein kinase 3D structures VprBP

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