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The Vpx\/Vpr family of lentiviral accessory proteins usurp the substrate receptor DCAF1 of host Cullin4-RING ligases (CRL4), a family of modular ubiquitin ligases involved in DNA replication, DNA repair and cell cycle regulation. CRL4\n                    <jats:sup>DCAF1<\/jats:sup>\n                    specificity modulation by Vpx and Vpr from certain simian immunodeficiency viruses (SIV) leads to recruitment, poly-ubiquitylation and subsequent proteasomal degradation of the host restriction factor SAMHD1, resulting in enhanced virus replication in differentiated cells. To unravel the mechanism of SIV Vpr-induced SAMHD1 ubiquitylation, we conducted integrative biochemical and structural analyses of the Vpr protein from SIVs infecting\n                    <jats:italic>Cercopithecus cephus<\/jats:italic>\n                    (SIV\n                    <jats:sub>mus<\/jats:sub>\n                    ). X-ray crystallography reveals commonalities between SIV\n                    <jats:sub>mus<\/jats:sub>\n                    Vpr and other members of the Vpx\/Vpr family with regard to DCAF1 interaction, while cryo-electron microscopy and cross-linking mass spectrometry highlight a divergent molecular mechanism of SAMHD1 recruitment. In addition, these studies demonstrate how SIV\n                    <jats:sub>mus<\/jats:sub>\n                    Vpr exploits the dynamic architecture of the multi-subunit CRL4\n                    <jats:sup>DCAF1<\/jats:sup>\n                    assembly to optimise SAMHD1 ubiquitylation. Together, the present work provides detailed molecular insight into variability and species-specificity of the evolutionary arms race between host SAMHD1 restriction and lentiviral counteraction through Vpx\/Vpr proteins.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009775","type":"journal-article","created":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T13:44:02Z","timestamp":1627911842000},"page":"e1009775","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2166-1222","authenticated-orcid":true,"given":"Sofia","family":"Banchenko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0402-8647","authenticated-orcid":true,"given":"Ferdinand","family":"Krupp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Gotthold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"B\u00fcrger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7709-6002","authenticated-orcid":true,"given":"Andrea","family":"Graziadei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9258-0150","authenticated-orcid":true,"given":"Francis J.","family":"O\u2019Reilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4692-0681","authenticated-orcid":true,"given":"Ludwig","family":"Sinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Ruda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juri","family":"Rappsilber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian M. 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