Limits...
Sequence alignment reveals possible MAPK docking motifs on HIV proteins.

Evans P, Sacan A, Ungar L, Tozeren A - PLoS ONE (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Genomics and Computational Biology and Department of Computer and Information Science, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

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.

Show MeSH

Related in: MedlinePlus

D-site pattern hits on HIV proteins.Hits for the standard MAPK docking sites, Da and Db, and the proposed MAPK docking sites patterns, Dc and Dd, are annotated in purple on multiple sequence alignments of HIV proteins MA, Nef, Rev, Tat, and Vif. Subtypes in each alignment are represented by different colors: A1 is pink, B is blue, and C is green. Note that motif annotations occur in roughly the same position within a virus subtype.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2812490&req=5

pone-0008942-g001: D-site pattern hits on HIV proteins.Hits for the standard MAPK docking sites, Da and Db, and the proposed MAPK docking sites patterns, Dc and Dd, are annotated in purple on multiple sequence alignments of HIV proteins MA, Nef, Rev, Tat, and Vif. Subtypes in each alignment are represented by different colors: A1 is pink, B is blue, and C is green. Note that motif annotations occur in roughly the same position within a virus subtype.

Mentions: Since ERK1/2 substrates were statistically enriched with MAPK docking motifs, we hypothesized that the presence of these docking sites on most sequences of HIV proteins MA, Nef, Rev, Tat, and Vif would explain their reported phosphorylation by ERK1/2. Therefore, we searched for the MAPK docking site patterns on HIV sequences gathered from the Los Alamos National Lab (LANL) HIV Sequence Database (http://www.hiv.lanl.gov/), which contains thousands of sequences spanning multiple subtypes and recombinant forms. In this analysis, we considered HIV strains with at least 50 sequences for all HIV proteins known to interact with ERK1/2, leaving three strains to consider: A1, B, and C. These subtypes are responsible for the majority of the HIV infection around the globe [21]. Figure 1 shows the Da and Db motif annotations on multiple sequence alignments of HIV proteins, and Table 2 shows the percentages of HIV subtype sequences with docking site matches. The results showed a subtype dependence for the annotations of the Da and Db patterns along HIV proteins.


Sequence alignment reveals possible MAPK docking motifs on HIV proteins.

Evans P, Sacan A, Ungar L, Tozeren A - PLoS ONE (2010)

D-site pattern hits on HIV proteins.Hits for the standard MAPK docking sites, Da and Db, and the proposed MAPK docking sites patterns, Dc and Dd, are annotated in purple on multiple sequence alignments of HIV proteins MA, Nef, Rev, Tat, and Vif. Subtypes in each alignment are represented by different colors: A1 is pink, B is blue, and C is green. Note that motif annotations occur in roughly the same position within a virus subtype.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2812490&req=5

pone-0008942-g001: D-site pattern hits on HIV proteins.Hits for the standard MAPK docking sites, Da and Db, and the proposed MAPK docking sites patterns, Dc and Dd, are annotated in purple on multiple sequence alignments of HIV proteins MA, Nef, Rev, Tat, and Vif. Subtypes in each alignment are represented by different colors: A1 is pink, B is blue, and C is green. Note that motif annotations occur in roughly the same position within a virus subtype.
Mentions: Since ERK1/2 substrates were statistically enriched with MAPK docking motifs, we hypothesized that the presence of these docking sites on most sequences of HIV proteins MA, Nef, Rev, Tat, and Vif would explain their reported phosphorylation by ERK1/2. Therefore, we searched for the MAPK docking site patterns on HIV sequences gathered from the Los Alamos National Lab (LANL) HIV Sequence Database (http://www.hiv.lanl.gov/), which contains thousands of sequences spanning multiple subtypes and recombinant forms. In this analysis, we considered HIV strains with at least 50 sequences for all HIV proteins known to interact with ERK1/2, leaving three strains to consider: A1, B, and C. These subtypes are responsible for the majority of the HIV infection around the globe [21]. Figure 1 shows the Da and Db motif annotations on multiple sequence alignments of HIV proteins, and Table 2 shows the percentages of HIV subtype sequences with docking site matches. The results showed a subtype dependence for the annotations of the Da and Db patterns along HIV proteins.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Genomics and Computational Biology and Department of Computer and Information Science, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

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.

Show MeSH
Related in: MedlinePlus