Vpr protein

Function

Vpr protein (Vpr) or viral protein R is a 96 amino acid protein which encoded by the human Immunodeficiency virus type 1 (HIV-1). HIV-1 genome includes nine genes, six of them are accessory proteins, including vpr. Vpr has several roles in the progression of acquired immunodeficiency syndrome (AIDS) disease, including regulation the HIV-1 pre-integration complex (PIC) nuclear import and virus replication in non-dividing macrophages^[1]. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects^[2].

Vpr induce cell cycle arrest by recruits cellular targets for degradation^[3]

One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of DNA damage–binding protein 1 (DDB1) and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex elucidate the molecular mechanism in which Vpr inhibits DDB1 enzymatic activity and send it for degradation.

• Vpr binding to the DCAF1 WD40 by its N-terminus and α3 helix.
  
• Vpr uses structural mimicry to DNA to engages UNG2.
  
• DCAF1 is anchored into DDB1 by a helix-loop-helix motif
  

Disease

HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency^[4]. For more details about AIDS disease see AIDS in Wikipedia

For details about another HIV-1 components and its replication pathway see HIV and accessory proteins.

Relevance

Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both vpr and vpx genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication^[4]. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy ^[2]

Conservation

Vpr is highly conserved in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates^[1]. In addition, all primate lentiviruses has vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - vpx. In these lentiviruses, vpr and vpx executes together the roles which HIV-1 vpr perform. Vpr and Vpx has low conservation between them.