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 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 elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation: DCAF1 WD40 domain by its N-terminus and α3 helix. In addition, by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to . It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

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

According to 2017, the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve^[5]. 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].

Structural highlights^[6]

Vpr structure is characterized by three well-defined α-helices: 17–33, 38–50 and 56–77 surrounded by flexible N and C-terminal domains. Vpr have been determined by NMR in the presence of 30% TFE several times, in 1esx, 1vpc and 1ceu structures. TFE is known to stabilize secondary structures and to prevent interactions between hydrophobic cores. However, the result was less globular structure than what it could be in reality. So, another NMR solution of Vpr is determined in the presence 10–30% of CD3CN, a less hydrophobic solvent, and in pure water. In this structure (1m8l), the structure folding around a hydrophobic core was improved, and can explain the binding properties of Vpr.

Conservation

Vpr is 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^[4]. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome^[3].