4CC9

Crystal structure of human SAMHD1 (amino acid residues 582-626) bound to Vpx isolated from sooty mangabey and human DCAF1 (amino acid residues 1058-1396)

Summary for 4CC9

• Entry DOI: 10.2210/pdb4cc9/pdb
• Descriptor: PROTEIN VPRBP, PROTEIN VPX, DEOXYNUCLEOSIDE TRIPHOSPHATE TRIPHOSPHOHYDROLASE SAMHD1, ... (6 entities in total)
• Functional Keywords: protein binding, hiv, siv, retroviral restriction factor, retroviral accessory protein, ubiquitination, proteasomal degradation
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm: Q9Y4B6; Virion: P19508; Nucleus : Q9Y3Z3
• Total number of polymer chains: 3
• Total formula weight: 63166.39

Authors

Schwefel, D.,Groom, H.C.T.,Boucherit, V.C.,Christodoulou, E.,Walker, P.A.,Stoye, J.P.,Bishop, K.N.,Taylor, I.A. (deposition date: 2013-10-19, release date: 2013-12-11, Last modification date: 2024-05-08)

Primary citation

Schwefel, D.,Groom, H.C.T.,Boucherit, V.C.,Christodoulou, E.,Walker, P.A.,Stoye, J.P.,Bishop, K.N.,Taylor, I.A.
Structural Basis of Lentiviral Subversion of a Cellular Protein Degradation Pathway.
Nature, 505:234-, 2014

PubMed 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 cells as well as resting CD4(+) T cells by reducing the cellular deoxynucleoside 5'-triphosphate (dNTP) concentration to a level at which the viral reverse transcriptase cannot function. 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 degradation. 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.

PubMed: 24336198
DOI: 10.1038/NATURE12815

Experimental method

X-RAY DIFFRACTION (2.473 Å)