title: Characterization of the interactions between SIVrcm Vpx and red-capped mangabey SAMHD1.
abstract: SAMHD1 (SAM domain- and HD domain-containing protein 1) inhibits HIV-1 infection of myeloid cells and resting CD4+ T-cells. Two lineages of primate lentiviruses, the sooty mangabey SIV (simian immunodeficiency virus) (SIVsm)/macaque SIV (SIVmac)/HIV-2 lineage and the red-capped mangabey SIV (SIVrcm) lineage, carry a SAMHD1 antagonist called Vpx. Vpx recognizes SAMHD1 and recruits a ubiquitin E3 ligase complex that is composed of CUL4 (Cullin4), DDB1 (damaged DNA-binding protein 1) and a member of the DCAF (DDB1/CUL4-associated factor) family called DCAF1. This E3 ligase complex polyubiquitinates SAMHD1, which leads to proteasomal degradation of SAMHD1. As opposed to the well-characterized interaction of SIVmac Vpx with human SAMHD1 and DCAF1, SIVrcm Vpx adopts a different mode of interaction with SAMHD1 of red-capped mangabeys. In the present study, we have characterized the interactions that are essential for SIVrcm Vpx-mediated degradation of rcmSAMHD1 (red-capped mangabey SAMHD1). Using mutagenesis and molecular modelling, we have determined the key role of the W23LHR26 peptide of SIVrcm Vpx in recognizing rcmSAMHD1. The amino acids Phe15, Leu36, Phe52, Arg55 and Arg56 at the N-terminal domain (NtD) of rcmSAMHD1 are involved in interaction with Vpxrcm (red-capped mangabey Vpx). The molecular model of rcmSAMHD1-NtD, Vpxrcm and C-terminal domain (CtD) of DCAF1 (DCAF1-CtD) complex reveals further that rcmSAMHD1-NtD and Vpxrcm utilize an interaction interface that is different from that used by human SAMHD1-CtD and Vpxsm. These findings provide further insights into the different modes of interaction between Vpx and SAMHD1 as the result of the 'arms race' of virus and host cell.
authors: *MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P.R. China.
authors: Jian
authors: J
authors: Li
authors: *MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P.R. China.
authors: Fengwen
authors: F
authors: Xu
authors: *MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P.R. China.
authors: Siqi
authors: S
authors: Hu
authors: †Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P.R. China.
authors: Jinming
authors: J
authors: Zhou
authors: *MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P.R. China.
authors: Shan
authors: S
authors: Mei
authors: *MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P.R. China.
authors: Xiaoxiao
authors: X
authors: Zhao
authors: †Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P.R. China.
authors: Shan
authors: S
authors: Cen
authors: *MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P.R. China.
authors: Qi
authors: Q
authors: Jin
authors: *MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P.R. China.
authors: Chen
authors: C
authors: Liang
authors: *MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P.R. China.
authors: Fei
authors: F
authors: Guo
mesh_terms: D000818:Animals; D016664:Cercocebus; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008958:Models, Molecular; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D059748:Proteolysis; D000076106:SAM Domain and HD Domain-Containing Protein 1; D015302:Simian Immunodeficiency Virus; D013045:Species Specificity; D054875:Ubiquitination; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*
chemical_list: C513059:VPX protein, Simian immunodeficiency virus; D054334:Viral Regulatory and Accessory Proteins; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins