Abstract:The protein kinase PKR activated by viral dsRNA, phosphorylates the eIF2α, which inhibit the mechanism of translation initiation. Viral evolved proteins mimicking the eIF2α block its phosphorylation and help in the viral replication. To decipher the molecular basis for the PKR’s substrate and inhibitor interaction mechanisms, we carried the molecular dynamics studies on the catalytic domain of PKR in complex with substrate eIF2α, and inhibitors TAT and K3L. The studies conducted show the altered domain movemen… Show more
“…6: 181095 or nearby, which have been shown to be enriched in positively selected sites [34]. aG helix and specifically positions with amino acid substitutions on the selected edge are involved in PKR interaction with eIF2a [35]; however, there is no evidence of bursts of evolution in eIF2a gene on the same edge.…”
Section: Resultsmentioning
confidence: 99%
“…Most substitutions lie in αD, αG and αH helices or nearby, which have been shown to be enriched in positively selected sites [34]. αG helix and specifically positions with amino acid substitutions on the selected edge are involved in PKR interaction with eIF2 α [35]; however, there is no evidence of bursts of evolution in eIF2α gene on the same edge. Figure 3.Alignment of PKR genes of Catarrhini (fragments) containing 18 non-synonymous substitutions on the internal edge ancestral to Macaca mulatta and Macaca fascicularis .…”
Evolution can occur both gradually and through alternating episodes of stasis and rapid changes. However, the prevalence and magnitude of fluctuations of the rate of evolution remain obscure. Detecting a rapid burst of changes requires a detailed record of past evolution, so that events that occurred within a short time interval can be identified. Here, we use the phylogenies of the Baikal Lake amphipods and of Catarrhini, which contain very short internal edges which make this task feasible. We detect six salient bursts of evolution of individual proteins during such short time periods, each involving between six and 38 amino acid substitutions. These bursts were extremely unlikely to have occurred neutrally, and were apparently caused by positive selection. On average, in the course of a time interval required for one synonymous substitution per site, a protein undergoes a strong burst of rapid evolution with probability at least approximately 0.01.
“…6: 181095 or nearby, which have been shown to be enriched in positively selected sites [34]. aG helix and specifically positions with amino acid substitutions on the selected edge are involved in PKR interaction with eIF2a [35]; however, there is no evidence of bursts of evolution in eIF2a gene on the same edge.…”
Section: Resultsmentioning
confidence: 99%
“…Most substitutions lie in αD, αG and αH helices or nearby, which have been shown to be enriched in positively selected sites [34]. αG helix and specifically positions with amino acid substitutions on the selected edge are involved in PKR interaction with eIF2 α [35]; however, there is no evidence of bursts of evolution in eIF2α gene on the same edge. Figure 3.Alignment of PKR genes of Catarrhini (fragments) containing 18 non-synonymous substitutions on the internal edge ancestral to Macaca mulatta and Macaca fascicularis .…”
Evolution can occur both gradually and through alternating episodes of stasis and rapid changes. However, the prevalence and magnitude of fluctuations of the rate of evolution remain obscure. Detecting a rapid burst of changes requires a detailed record of past evolution, so that events that occurred within a short time interval can be identified. Here, we use the phylogenies of the Baikal Lake amphipods and of Catarrhini, which contain very short internal edges which make this task feasible. We detect six salient bursts of evolution of individual proteins during such short time periods, each involving between six and 38 amino acid substitutions. These bursts were extremely unlikely to have occurred neutrally, and were apparently caused by positive selection. On average, in the course of a time interval required for one synonymous substitution per site, a protein undergoes a strong burst of rapid evolution with probability at least approximately 0.01.
“…Most substitutions lie in αD, αG and αH helices or nearby, which have been shown to be enriched in positively selected sites (Rothenburg et al, 2009). αG helix and specifically positions with amino acid substitutions on the selected edge are involved in PKR interaction with eIF2α (Krishna et al, 2016); however, there is no evidence of bursts of evolution in eIF2α gene on the same edge.…”
Evolution can occur both gradually and through alternating episodes of stasis and rapid changes. However, the prevalence and magnitude of fluctuations of the rate of evolution remains obscure. Detecting a rapid burst of changes requires a detailed record of past evolution, so that events that occurred within a short time interval can be identified. Here, we use the phylogenies of the Baikal Lake amphipods and of Catarrhini, which contain very short internal edges facilitating this task. We detect 6 radical bursts of evolution of individual proteins during such short time periods, each involving between 6 and 38 amino acid substitutions. These bursts were extremely unlikely to have occurred neutrally, and were apparently caused by positive selection. On average, in the course of a time interval required for one synonymous substitution per site, a protein undergoes a strong burst of rapid evolution with probability at least ~0.01.
“…Tat is known to compete with the translational regulator eIF2a as a substrate of PKR to promote viral mRNA translation in infected cells as previously reviewed [100]. The interaction between Tat 86 and PKR is predicted to occur by the formation of several electrostatic, aromatic, and hydrogen bonds between amino acid interfaces of each protein [101]. Of these predicted bonds, the involvement of Tat residues Lys 19, Lys28, Lys29, Lys 51, and Lys71 in salt bridge formation and Lys41 in aromatic interactions with PKR are of interest, as the alteration of these residues could negatively affect LTR transactivation and affect the stability of the Tat-PKR interaction [101].…”
Section: Effects Of Tat Variation On Phosphorylation Of Tat-becausementioning
confidence: 99%
“…The interaction between Tat 86 and PKR is predicted to occur by the formation of several electrostatic, aromatic, and hydrogen bonds between amino acid interfaces of each protein [101]. Of these predicted bonds, the involvement of Tat residues Lys 19, Lys28, Lys29, Lys 51, and Lys71 in salt bridge formation and Lys41 in aromatic interactions with PKR are of interest, as the alteration of these residues could negatively affect LTR transactivation and affect the stability of the Tat-PKR interaction [101]. PKR has been shown to phosphorylate residues Ser46, Ser62, Thr64, and Ser68, all of which are located in either Tat's core domain or glutamate-rich domain [99,58,102,93] (Figure 2).…”
Section: Effects Of Tat Variation On Phosphorylation Of Tat-becausementioning
Human immunodeficiency virus type 1 (HIV-1) encodes a transactivator of transcription (Tat) protein, which has several functions that promote viral replication, pathogenesis, and disease. Amino acid variation within Tat has been observed to alter the functional properties of Tat and, depending on the HIV-1 subtype, may produce Tat phenotypes differing from viruses representative of each subtype and commonly used in in vivo and in vitro experimentation. The molecular properties of Tat allow for distinctive functional activities to be determined such as the subcellular localization and other intra-and extracellular functional aspects of this important viral protein influenced by variation within the Tat sequence. Once Tat has been transported into the nucleus and becomes engaged in transactivation of the long terminal repeat (LTR), various Tat variants may differ in their capacity to activate viral transcription. Post-translational modification patterns based on these amino acid variations may alter interactions between Tat and host factors, which may positively or negatively affect this process. Additionally, the ability of HIV-1 to utilize or not utilize the transactivation response (TAR) element within the LTR, based on genetic variation and cellular phenotype, adds a layer of complexity to the processes that govern Tatmediated proviral DNA-driven transcription and replication. In contrast, cytoplasmic or extracellular localization of Tat may cause pathogenic effects in the form of altered cell activation, apoptosis, or neurotoxicity. Tat variants have been shown to differentially induce these processes, which may have implications for long-term HIV-1-infected patient care in the antiretroviral therapy era. Future studies concerning genetic variation of Tat with respect to function should focus on variants derived from HIV-1-infected individuals to efficiently guide Tat-targeted therapies and elucidate mechanisms of pathogenesis within the global patient population.
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