Structural Basis of Clade-specific Engagement of SAMHD1 (Sterile α Motif and Histidine/Aspartate-containing Protein 1) Restriction Factors by Lentiviral Viral Protein X (Vpx) Virulence Factors

Wu, Ying; Koharudin, Leonardus M. I.; Mehrens, Jennifer; DeLucia, Maria; Byeon, Chang-Hyeok; Byeon, In-Ja L.; Calero, Guillermo; Ahn, Jinwoo; Gronenborn, Angela M.

doi:10.1074/jbc.M115.665513

Title: Structural Basis of Clade-specific Engagement of SAMHD1 (Sterile α Motif and Histidine/Aspartate-containing Protein 1) Restriction Factors by Lentiviral Viral Protein X (Vpx) Virulence Factors

Journal Article · Thu Jun 04 00:00:00 EDT 2015 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M115.665513· OSTI ID:1245873

Wu, Ying ^[1]; Koharudin, Leonardus M. I. ^[1]; Mehrens, Jennifer ^[1]; DeLucia, Maria ^[1]; Byeon, Chang-Hyeok ^[1]; Byeon, In-Ja L. ^[1]; Calero, Guillermo ^[1]; Ahn, Jinwoo ^[1]; Gronenborn, Angela M. ^[1]

Univ. of Pittsburgh School of Medicine, PA (United States)

Sterile α motif (SAM) and histidine/aspartate (HD)-containing protein 1 (SAMHD1) restricts human/simian immunodeficiency virus 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 co-evolution 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: the SAMHD1 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. Furthermore, we show that changing the single Ser-52 in human SAMHD1 to Phe, the residue found in SAMHD1 of Red-capped monkey and Mandrill, 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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: P50GM082251

OSTI ID:: 1245873

Journal Information:: Journal of Biological Chemistry, Vol. 290, Issue 29; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 9 works

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The DDB1–DCAF1–Vpr–UNG2 crystal structure reveals how HIV-1 Vpr steers human UNG2 toward destruction Wu, Ying; Zhou, Xiaohong; Barnes, Christopher O. Nature Structural & Molecular Biology, Vol. 23, Issue 10 https://doi.org/10.1038/nsmb.3284	journal	August 2016
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Title: Structural Basis of Clade-specific Engagement of SAMHD1 (Sterile α Motif and Histidine/Aspartate-containing Protein 1) Restriction Factors by Lentiviral Viral Protein X (Vpx) Virulence Factors

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