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Structural basis of lentiviral subversion of a cellular protein degradation pathway

DOI: 10.1038/nature12815 DOI Help
PMID: 24336198 PMID Help

Authors: David Schwefel (MRC National Institute for Medical Research) , Harriet C. T. Groom (MRC National Institute for Medical Research) , Virginie C. Boucherit (MRC National Institute for Medical Research) , Evangelos Christodoulou (MRC National Institute for Medical Research) , Philip A. Walker (MRC National Institute for Medical Research) , Jonathan P. Stoye (MRC National Institute for Medical Research) , Kate N. Bishop (MRC National Institute for Medical Research) , Ian A. Taylor (MRC National Institute for Medical Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 505 (7482) , PAGES 234 - 238

State: Published (Approved)
Published: December 2013
Diamond Proposal Number(s): 7707

Abstract: Lentiviruses contain accessory genes that have evolved to counteract the effects of host cellular defence proteins that inhibit productive infection. One such restriction factor, SAMHD1, inhibits human immunodeficiency virus (HIV)-1 infection of myeloid-lineage cells1, 2 as well as resting CD4+ T cells3, 4 by reducing the cellular deoxynucleoside 5′-triphosphate (dNTP) concentration to a level at which the viral reverse transcriptase cannot function5, 6. In other lentiviruses, including HIV-2 and related simian immunodeficiency viruses (SIVs), SAMHD1 restriction is overcome by the action of viral accessory protein x (Vpx) or the related viral protein r (Vpr) that target and recruit SAMHD1 for proteasomal degradation7, 8. The molecular mechanism by which these viral proteins are able to usurp the host cell’s ubiquitination machinery to destroy the cell’s protection against these viruses has not been defined. Here we present the crystal structure of a ternary complex of Vpx with the human E3 ligase substrate adaptor DCAF1 and the carboxy-terminal region of human SAMHD1. Vpx is made up of a three-helical bundle stabilized by a zinc finger motif, and wraps tightly around the disc-shaped DCAF1 molecule to present a new molecular surface. This adapted surface is then able to recruit SAMHD1 via its C terminus, making it a competent substrate for the E3 ligase to mark for proteasomal degradation. The structure reported here provides a molecular description of how a lentiviral accessory protein is able to subvert the cell’s normal protein degradation pathway to inactivate the cellular viral defence system.

Journal Keywords: Animals; Carrier; Cercocebus; Crystallography; X-Ray; HIV; Host-Pathogen; Humans; Models; Molecular; Monomeric; Proteasome; Proteolysis; Simian; Ubiquitination; Viral; vpr; Human Immunodeficiency Virus

Diamond Keywords: Human Immunodeficiency Virus (HIV); Viruses

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 26/01/2014 10:58

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)