Abstract
Over the course of HIV infection, virus replication is facilitated by the phosphorylation of HIV proteins by human ERK1 and ERK2 mitogen-activated protein kinases (MAPKs). MAPKs are known to phosphorylate their substrates by first binding with them at a docking site. Docking site interactions could be viable drug targets because the sequences guiding them are more specific than phosphorylation consensus sites. In this study we use multiple bioinformatics tools to discover candidate MAPK docking site motifs on HIV proteins known to be phosphorylated by MAPKs, and we discuss the possibility of targeting docking sites with drugs. Using sequence alignments of HIV proteins of different subtypes, we show that MAPK docking patterns previously described for human proteins appear on the HIV matrix, Tat, and Vif proteins in a strain dependent manner, but are absent from HIV Rev and appear on all HIV Nef strains. We revise the regular expressions of previously annotated MAPK docking patterns in order to provide a subtype independent motif that annotates all HIV proteins. One revision is based on a documented human variant of one of the substrate docking motifs, and the other reduces the number of required basic amino acids in the standard docking motifs from two to one. The proposed patterns are shown to be consistent with in silico docking between ERK1 and the HIV matrix protein. The motif usage on HIV proteins is sufficiently different from human proteins in amino acid sequence similarity to allow for HIV specific targeting using small-molecule drugs.
Highlights
ERK1 and ERK2 mitogen-activated protein kinases (MAPKs) have been shown to increase HIV infectivity by phosphorylating a subset of HIV proteins [1]
In this study we have shown that known MAPK docking motifs occur in a strain dependent manner on HIV proteins known to interact with human ERK1/2
While the detailed role of MAPK phosphorylation in HIV infection has not been established in a clinical setting, ERK1/2 phosphorylation of HIV proteins has been associated with viral infectivity in a number of in vitro studies, highlighting the importance of MAPK docking sites in the course of HIV infection
Summary
ERK1 and ERK2 mitogen-activated protein kinases (MAPKs) have been shown to increase HIV infectivity by phosphorylating a subset of HIV proteins [1]. Viral replication may require the phosphorylation of the HIV viral infectivity factor (Vif) by ERK1 or ERK2 [3]. Nef and Tat have been shown to induce the ERK MAPK cascade [4,5]. ERK1/2 has been shown to phosphorylate HIV Nef, Rev, and Tat in vitro [1], but the roles of these phosphorylation events in HIV infectivity remain unknown [6]. The inhibition of MAPK phosphorylation has been shown to decrease HIV infectivity, indicating that MA and Vif MAPK-directed phosphorylation events would make good drug targets [1,2]
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