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Detecting remote sequence homology in disordered proteins: discovery of conserved motifs in the N-termini of Mononegavirales phosphoproteins.

Karlin D, Belshaw R - PLoS ONE (2012)

Bottom Line: We now compared the N-termini using sensitive sequence similarity search programs, able to detect residual similarities unnoticeable by conventional approaches.Despite its short length (11-16aa), several arguments allow us to conclude that soyuz1 probably evolved by homologous descent, unlike linear motifs.Our results suggest several testable hypotheses regarding the replication of Mononegavirales and suggest that disordered regions with little overall sequence similarity, common in viral and eukaryotic proteins, might contain currently overlooked motifs (intermediate in length between linear motifs and disordered domains) that could be detected simply by comparing orthologous proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Oxford, Oxford, United Kingdom. david.karlin@zoo.ox.ac.uk

ABSTRACT
Paramyxovirinae are a large group of viruses that includes measles virus and parainfluenza viruses. The viral Phosphoprotein (P) plays a central role in viral replication. It is composed of a highly variable, disordered N-terminus and a conserved C-terminus. A second viral protein alternatively expressed, the V protein, also contains the N-terminus of P, fused to a zinc finger. We suspected that, despite their high variability, the N-termini of P/V might all be homologous; however, using standard approaches, we could previously identify sequence conservation only in some Paramyxovirinae. We now compared the N-termini using sensitive sequence similarity search programs, able to detect residual similarities unnoticeable by conventional approaches. We discovered that all Paramyxovirinae share a short sequence motif in their first 40 amino acids, which we called soyuz1. Despite its short length (11-16aa), several arguments allow us to conclude that soyuz1 probably evolved by homologous descent, unlike linear motifs. Conservation across such evolutionary distances suggests that soyuz1 plays a crucial role and experimental data suggest that it binds the viral nucleoprotein to prevent its illegitimate self-assembly. In some Paramyxovirinae, the N-terminus of P/V contains a second motif, soyuz2, which might play a role in blocking interferon signaling. Finally, we discovered that the P of related Mononegavirales contain similarly overlooked motifs in their N-termini, and that their C-termini share a previously unnoticed structural similarity suggesting a common origin. Our results suggest several testable hypotheses regarding the replication of Mononegavirales and suggest that disordered regions with little overall sequence similarity, common in viral and eukaryotic proteins, might contain currently overlooked motifs (intermediate in length between linear motifs and disordered domains) that could be detected simply by comparing orthologous proteins.

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Alignments of the N-termini of P from Pneumovirinae, Filoviridae and Rhabdoviridae.Conventions as in Figure 2. Abbreviations and accession numbers are in Table 2. (A) Mir motif of Pneumovirinae. A1 – Alignment of the N-terminus of P of both metapneumoviruses and pneumoviruses. A2 – Same alignment as in A1 but restricted to metapneumoviruses. Positions corresponding to soyuz1 are indicated above the alignment. The coloring of sequence conservation is different from A1 since conservation is now based only on the two metapneumovirus sequences. (B) Sputnik motif of Filoviridae. The asterisk indicates the newly published sequence of LLoviu virus. (C) N-termini of the P of two Rhabdoviridae genera: lyssavirus and vesiculovirus. A disputed L-binding site in lyssavirus P is indicated [108]. The boundaries of the N°-binding region of VSV P were obtained from the crystal structure of N°-P [58].
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pone-0031719-g008: Alignments of the N-termini of P from Pneumovirinae, Filoviridae and Rhabdoviridae.Conventions as in Figure 2. Abbreviations and accession numbers are in Table 2. (A) Mir motif of Pneumovirinae. A1 – Alignment of the N-terminus of P of both metapneumoviruses and pneumoviruses. A2 – Same alignment as in A1 but restricted to metapneumoviruses. Positions corresponding to soyuz1 are indicated above the alignment. The coloring of sequence conservation is different from A1 since conservation is now based only on the two metapneumovirus sequences. (B) Sputnik motif of Filoviridae. The asterisk indicates the newly published sequence of LLoviu virus. (C) N-termini of the P of two Rhabdoviridae genera: lyssavirus and vesiculovirus. A disputed L-binding site in lyssavirus P is indicated [108]. The boundaries of the N°-binding region of VSV P were obtained from the crystal structure of N°-P [58].

Mentions: Other Mononegavirales P have an organization similar to that of Paramyxovirinae, shown in Figure 1. We found that the P of most Mononegavirales have an N-terminal “tip” with features similar to those of soyuz1, i.e. a low variability and one or two predicted secondary structure elements located upstream of a variable region devoid of predicted secondary structure. In particular, all Pneumovirinae P have a conserved N-terminal motif, which we called mir (Figure 8A). Likewise, the P of all Filoviridae have a conserved N-terminal motif (Figure 8B), which we called sputnik (we could not find previous descriptions of these motifs in the literature). The similarity between the mir motif of metapneumovirus and pneumovirus P was not significant (E = 1.4×10−3), while the similarity between the sputnik motif of ebolaviruses and Marburg virus was significant (E = 1.4×10−7). Interestingly, while this manuscript was in preparation, the sequence of a new Filoviridae, LLoviu virus, was published [57], and it also contains the sputnik motif (Figure 8B).


Detecting remote sequence homology in disordered proteins: discovery of conserved motifs in the N-termini of Mononegavirales phosphoproteins.

Karlin D, Belshaw R - PLoS ONE (2012)

Alignments of the N-termini of P from Pneumovirinae, Filoviridae and Rhabdoviridae.Conventions as in Figure 2. Abbreviations and accession numbers are in Table 2. (A) Mir motif of Pneumovirinae. A1 – Alignment of the N-terminus of P of both metapneumoviruses and pneumoviruses. A2 – Same alignment as in A1 but restricted to metapneumoviruses. Positions corresponding to soyuz1 are indicated above the alignment. The coloring of sequence conservation is different from A1 since conservation is now based only on the two metapneumovirus sequences. (B) Sputnik motif of Filoviridae. The asterisk indicates the newly published sequence of LLoviu virus. (C) N-termini of the P of two Rhabdoviridae genera: lyssavirus and vesiculovirus. A disputed L-binding site in lyssavirus P is indicated [108]. The boundaries of the N°-binding region of VSV P were obtained from the crystal structure of N°-P [58].
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3293882&req=5

pone-0031719-g008: Alignments of the N-termini of P from Pneumovirinae, Filoviridae and Rhabdoviridae.Conventions as in Figure 2. Abbreviations and accession numbers are in Table 2. (A) Mir motif of Pneumovirinae. A1 – Alignment of the N-terminus of P of both metapneumoviruses and pneumoviruses. A2 – Same alignment as in A1 but restricted to metapneumoviruses. Positions corresponding to soyuz1 are indicated above the alignment. The coloring of sequence conservation is different from A1 since conservation is now based only on the two metapneumovirus sequences. (B) Sputnik motif of Filoviridae. The asterisk indicates the newly published sequence of LLoviu virus. (C) N-termini of the P of two Rhabdoviridae genera: lyssavirus and vesiculovirus. A disputed L-binding site in lyssavirus P is indicated [108]. The boundaries of the N°-binding region of VSV P were obtained from the crystal structure of N°-P [58].
Mentions: Other Mononegavirales P have an organization similar to that of Paramyxovirinae, shown in Figure 1. We found that the P of most Mononegavirales have an N-terminal “tip” with features similar to those of soyuz1, i.e. a low variability and one or two predicted secondary structure elements located upstream of a variable region devoid of predicted secondary structure. In particular, all Pneumovirinae P have a conserved N-terminal motif, which we called mir (Figure 8A). Likewise, the P of all Filoviridae have a conserved N-terminal motif (Figure 8B), which we called sputnik (we could not find previous descriptions of these motifs in the literature). The similarity between the mir motif of metapneumovirus and pneumovirus P was not significant (E = 1.4×10−3), while the similarity between the sputnik motif of ebolaviruses and Marburg virus was significant (E = 1.4×10−7). Interestingly, while this manuscript was in preparation, the sequence of a new Filoviridae, LLoviu virus, was published [57], and it also contains the sputnik motif (Figure 8B).

Bottom Line: We now compared the N-termini using sensitive sequence similarity search programs, able to detect residual similarities unnoticeable by conventional approaches.Despite its short length (11-16aa), several arguments allow us to conclude that soyuz1 probably evolved by homologous descent, unlike linear motifs.Our results suggest several testable hypotheses regarding the replication of Mononegavirales and suggest that disordered regions with little overall sequence similarity, common in viral and eukaryotic proteins, might contain currently overlooked motifs (intermediate in length between linear motifs and disordered domains) that could be detected simply by comparing orthologous proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Oxford, Oxford, United Kingdom. david.karlin@zoo.ox.ac.uk

ABSTRACT
Paramyxovirinae are a large group of viruses that includes measles virus and parainfluenza viruses. The viral Phosphoprotein (P) plays a central role in viral replication. It is composed of a highly variable, disordered N-terminus and a conserved C-terminus. A second viral protein alternatively expressed, the V protein, also contains the N-terminus of P, fused to a zinc finger. We suspected that, despite their high variability, the N-termini of P/V might all be homologous; however, using standard approaches, we could previously identify sequence conservation only in some Paramyxovirinae. We now compared the N-termini using sensitive sequence similarity search programs, able to detect residual similarities unnoticeable by conventional approaches. We discovered that all Paramyxovirinae share a short sequence motif in their first 40 amino acids, which we called soyuz1. Despite its short length (11-16aa), several arguments allow us to conclude that soyuz1 probably evolved by homologous descent, unlike linear motifs. Conservation across such evolutionary distances suggests that soyuz1 plays a crucial role and experimental data suggest that it binds the viral nucleoprotein to prevent its illegitimate self-assembly. In some Paramyxovirinae, the N-terminus of P/V contains a second motif, soyuz2, which might play a role in blocking interferon signaling. Finally, we discovered that the P of related Mononegavirales contain similarly overlooked motifs in their N-termini, and that their C-termini share a previously unnoticed structural similarity suggesting a common origin. Our results suggest several testable hypotheses regarding the replication of Mononegavirales and suggest that disordered regions with little overall sequence similarity, common in viral and eukaryotic proteins, might contain currently overlooked motifs (intermediate in length between linear motifs and disordered domains) that could be detected simply by comparing orthologous proteins.

Show MeSH
Related in: MedlinePlus