Modulating the activity of the channel-forming segment of Vpr protein from HIV-1

Abstract

Viral protein of regulation (Vpr) encoded by human immunodeficiency virus type 1 (HIV-1) is a short auxiliary protein that is 96 amino acids in length. During the viral life cycle, Vpr is released into the blood serum and is able to enter cellular membranes of noninfected cells. In this study a short peptide, Vpr(55-83), was shown to exhibit ion-channel-like activity when reconstituted into (1) planar lipid bilayers and (2) lipid bilayers held at the tip of a glass pipette. The two set-ups led to differences in the oligomerization state of the peptide, which was reflected in differences in the conductance levels. Experiments under applied hydrostatic pressure affect the dynamics of the protein within the membrane.

HIV-1 Vpr Triggers Mitochondrial Destruction by Impairing Mfn2-Mediated ER-Mitochondria Interaction

“…On the contrary, they showed that the toxic effect of Vpr was on the MOM, probably on Bax-targeting proteins [38]. Interestingly, the presence of a potential C-terminal TMD suggests that Vpr is a tail-anchored protein, which could be located on the ER and the MOM [11], [14], [16], [39], [40], [41]. Our results of protease protection support their findings in which Vpr is an integral protein with the N-terminus facing the cytoplasm.…”

“…Several lines of evidence have suggested that the killing of cells by Vpr might be the result of targeting mitochondria through a direct interaction with adenine nucleotide translocator (ANT) on the mitochondrial inner membrane to permeabilize mitochondrial membrane and release cytochrome c [7], [8], [9], [10], [11]. However, silencing of ANT had no effect on Vpr-induced apoptosis whereas knockdown of Bax suppressed it [12].…”

“…However, silencing of ANT had no effect on Vpr-induced apoptosis whereas knockdown of Bax suppressed it [12]. In addition, Vpr was shown to form an ion channel in vitro via its hydrophobic segment (amino acids 55–83) [8], [11] penetrating phospholipid bilayers [8], [11], [13]. Moreover, the configuration of Vpr C-terminal transmembrane domain (TMD) is similar to that of certain viral proteins, such as Myxoma virus M11L protein, vaccinia virus F1L protein, Epstein-Barr virus BHRF-1 protein and hepatitis C virus core protein.…”

“…Moreover, the configuration of Vpr C-terminal transmembrane domain (TMD) is similar to that of certain viral proteins, such as Myxoma virus M11L protein, vaccinia virus F1L protein, Epstein-Barr virus BHRF-1 protein and hepatitis C virus core protein. The C-terminal hydrophobic segments of these viral proteins contain mitochondrial targeting sequences (MTS), which are homologous to tail-anchored proteins [11], [13], [14], [15], [16], [17], [18]. The major feature of these proteins is that they all have one membrane anchor at the C-terminus, comprising one helical hydrophobic domain of 12 to 24 amino acids followed by positively charged amino acids [19], [20], [21].…”

Identification and molecular characterization of SIV Vpr R50G mutation associated with long term survival in SIV-infected morphine dependent and control macaques

“…While both WT SIV Vpr and R50G were associated with tetrapyrrole binding activity, SIV Vpr R50G was also predicted to have intramolecular lyase activity and was not predicted to have ion channel, oxidoreductase, and heme-copper terminal oxidase activity, among others. Previous studies have demonstrated that Vpr forms ion channels in vitro via its hydrophobic segment (amino acids 55–83) penetrating phospholipid bilayers (Chen et al, 2010; Piller et al, 1996; Wecker et al, 2002) and thus it is easy to assume, as has been demonstrated, that Vpr exerts an effect at the level of nuclear and cell membranes (de Noronha et al, 2001). Changes in Vpr that alter any of the Vpr-specific activities would have a negative impact on viral survival and thus could potentially slow down disease progression.…”