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Tryptogalinin is a tick Kunitz serine protease inhibitor with a unique intrinsic disorder.

Valdés JJ, Schwarz A, Cabeza de Vaca I, Calvo E, Pedra JH, Guallar V, Kotsyfakis M - PLoS ONE (2013)

Bottom Line: Using homology-based modeling (and other protein prediction programs) we were able to model and explain the multifaceted function of tryptogalinin.The N-terminus of the modeled tryptogalinin is detached from the rest of the peptide and exhibits intrinsic disorder allowing an increased flexibility for its high affinity with its inhibiting partners (i.e., serine proteases).By incorporating experimental and computational methods our data not only describes the function of a Kunitz peptide from Ixodes scapularis, but also allows us to hypothesize about the molecular basis of this function at the atomic level.

View Article: PubMed Central - PubMed

Affiliation: Institute of Parasitology, Biology Centre of the Academy of Sciences of the Czech Republic, České Budějovice, Czech Republic. valdjj@gmail.com

ABSTRACT

Background: A salivary proteome-transcriptome project on the hard tick Ixodes scapularis revealed that Kunitz peptides are the most abundant salivary proteins. Ticks use Kunitz peptides (among other salivary proteins) to combat host defense mechanisms and to obtain a blood meal. Most of these Kunitz peptides, however, remain functionally uncharacterized, thus limiting our knowledge about their biochemical interactions.

Results: We discovered an unusual cysteine motif in a Kunitz peptide. This peptide inhibits several serine proteases with high affinity and was named tryptogalinin due to its high affinity for β-tryptase. Compared with other functionally described peptides from the Acari subclass, we showed that tryptogalinin is phylogenetically related to a Kunitz peptide from Rhipicephalus appendiculatus, also reported to have a high affinity for β-tryptase. Using homology-based modeling (and other protein prediction programs) we were able to model and explain the multifaceted function of tryptogalinin. The N-terminus of the modeled tryptogalinin is detached from the rest of the peptide and exhibits intrinsic disorder allowing an increased flexibility for its high affinity with its inhibiting partners (i.e., serine proteases).

Conclusions: By incorporating experimental and computational methods our data not only describes the function of a Kunitz peptide from Ixodes scapularis, but also allows us to hypothesize about the molecular basis of this function at the atomic level.

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A–C. Intrinsic protein disorder and MD simulations.Intrinsic regional protein disorder (A) predicted by the GeneSilico MetaServer [37] for tryptogalinin, TdPI (PDB: 2UUY chain: B) and BPTI (PDB: 5PTI), respectively – ‘D’ represents the disordered region and dashes are ordered. A total of 100 snapshots (i.e., conformations) during last 40 ns of MD for TdPI (B) and tryptogalinin (C).
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pone-0062562-g006: A–C. Intrinsic protein disorder and MD simulations.Intrinsic regional protein disorder (A) predicted by the GeneSilico MetaServer [37] for tryptogalinin, TdPI (PDB: 2UUY chain: B) and BPTI (PDB: 5PTI), respectively – ‘D’ represents the disordered region and dashes are ordered. A total of 100 snapshots (i.e., conformations) during last 40 ns of MD for TdPI (B) and tryptogalinin (C).

Mentions: The loop region L2 of tryptogalinin is similar to classical Kunitz peptides (eleven residues, as in BPTI tharegional protein disorder (A) predictedt has twelve) distinguishing tryptogalinin from TdPI (with only eight residues). Both L1 and L2 are thIntrinsic regional protein disordere main determinants on forming the Kunitz head that interacts with the active site of serine proteases [5]. Another main characteristic that distinguishes tryptogalinin from the majority of Kunitz peptides (including TdPI) is that the N-terminus (L1) is detached from the rest of the peptide due its lack of the first disulfide bridge, a unique structural distinction between the two peptides. This regional difference also translates into a high regional disorder as predicted by the MetaDisorder server [78] compared with TdPI and BPTI (Figure 6A). (MetaDisorder uses 12 separate programs and builds a consensus to predict protein disorder.)


Tryptogalinin is a tick Kunitz serine protease inhibitor with a unique intrinsic disorder.

Valdés JJ, Schwarz A, Cabeza de Vaca I, Calvo E, Pedra JH, Guallar V, Kotsyfakis M - PLoS ONE (2013)

A–C. Intrinsic protein disorder and MD simulations.Intrinsic regional protein disorder (A) predicted by the GeneSilico MetaServer [37] for tryptogalinin, TdPI (PDB: 2UUY chain: B) and BPTI (PDB: 5PTI), respectively – ‘D’ represents the disordered region and dashes are ordered. A total of 100 snapshots (i.e., conformations) during last 40 ns of MD for TdPI (B) and tryptogalinin (C).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3643938&req=5

pone-0062562-g006: A–C. Intrinsic protein disorder and MD simulations.Intrinsic regional protein disorder (A) predicted by the GeneSilico MetaServer [37] for tryptogalinin, TdPI (PDB: 2UUY chain: B) and BPTI (PDB: 5PTI), respectively – ‘D’ represents the disordered region and dashes are ordered. A total of 100 snapshots (i.e., conformations) during last 40 ns of MD for TdPI (B) and tryptogalinin (C).
Mentions: The loop region L2 of tryptogalinin is similar to classical Kunitz peptides (eleven residues, as in BPTI tharegional protein disorder (A) predictedt has twelve) distinguishing tryptogalinin from TdPI (with only eight residues). Both L1 and L2 are thIntrinsic regional protein disordere main determinants on forming the Kunitz head that interacts with the active site of serine proteases [5]. Another main characteristic that distinguishes tryptogalinin from the majority of Kunitz peptides (including TdPI) is that the N-terminus (L1) is detached from the rest of the peptide due its lack of the first disulfide bridge, a unique structural distinction between the two peptides. This regional difference also translates into a high regional disorder as predicted by the MetaDisorder server [78] compared with TdPI and BPTI (Figure 6A). (MetaDisorder uses 12 separate programs and builds a consensus to predict protein disorder.)

Bottom Line: Using homology-based modeling (and other protein prediction programs) we were able to model and explain the multifaceted function of tryptogalinin.The N-terminus of the modeled tryptogalinin is detached from the rest of the peptide and exhibits intrinsic disorder allowing an increased flexibility for its high affinity with its inhibiting partners (i.e., serine proteases).By incorporating experimental and computational methods our data not only describes the function of a Kunitz peptide from Ixodes scapularis, but also allows us to hypothesize about the molecular basis of this function at the atomic level.

View Article: PubMed Central - PubMed

Affiliation: Institute of Parasitology, Biology Centre of the Academy of Sciences of the Czech Republic, České Budějovice, Czech Republic. valdjj@gmail.com

ABSTRACT

Background: A salivary proteome-transcriptome project on the hard tick Ixodes scapularis revealed that Kunitz peptides are the most abundant salivary proteins. Ticks use Kunitz peptides (among other salivary proteins) to combat host defense mechanisms and to obtain a blood meal. Most of these Kunitz peptides, however, remain functionally uncharacterized, thus limiting our knowledge about their biochemical interactions.

Results: We discovered an unusual cysteine motif in a Kunitz peptide. This peptide inhibits several serine proteases with high affinity and was named tryptogalinin due to its high affinity for β-tryptase. Compared with other functionally described peptides from the Acari subclass, we showed that tryptogalinin is phylogenetically related to a Kunitz peptide from Rhipicephalus appendiculatus, also reported to have a high affinity for β-tryptase. Using homology-based modeling (and other protein prediction programs) we were able to model and explain the multifaceted function of tryptogalinin. The N-terminus of the modeled tryptogalinin is detached from the rest of the peptide and exhibits intrinsic disorder allowing an increased flexibility for its high affinity with its inhibiting partners (i.e., serine proteases).

Conclusions: By incorporating experimental and computational methods our data not only describes the function of a Kunitz peptide from Ixodes scapularis, but also allows us to hypothesize about the molecular basis of this function at the atomic level.

Show MeSH