Predicting the reactivity of proteins from their sequence alone: Kazal family of protein inhibitors of serine proteinases

Lu, Stephen; Lu, Wuyuan; Qasim, M.A.; Anderson, Stephen; Apostoł, Izydor; Ardelt, Wojciech; Bigler, Theresa L.; Chiang, Yiwen; Cook, James D.; James, Michael N.G.; Kato, Ikuo; Kelly, Clyde A.; Kohr, William J.; Komiyama, Tomoko; Lin, Tiao Yin; Ogawa, Michio; Otlewski, Jacek; Park, Soon Jae; Qasim, Sabiha; Ranjbar, Michael; Tashiro, Misao; Warne, Nicholas W.; Whatley, Harry; Wieczorek, A.; Wieczorek, Maciej; Wilusz, Tadeusz; Wynn, Richard; Zhang, Wenlei; Laskowski, M.

doi:10.1073/pnas.98.4.1410

Cited by 82 publications

(104 citation statements)

References 47 publications

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“…It can generate aberrant mutational data at positions where the side chains interact, a major known cause of non-additivity of mutational effects in proteins (78,79). To accurately dissect functional contributions of interacting residues in a protein, double mutations need to be introduced (53,63). As Trp-26 makes contacts with several neighboring residues, it remains interesting to examine the activity of some double mutants of HNP1 in future studies.…”

Section: Discussionmentioning

confidence: 99%

Trp-26 Imparts Functional Versatility to Human α-Defensin HNP1

Wei

Pazgier

Leeuw

et al. 2010

Journal of Biological Chemistry

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We performed a comprehensive alanine scan of human ␣-defensin HNP1 and tested the ability of the resulting analogs to kill Staphylococcus aureus, inhibit anthrax lethal factor, and bind human immunodeficiency virus-1 gp120. By far, the most deleterious mutation for all of these functions was W26A. The activities lost by W26A-HNP1 were restored progressively by replacing W26 with non-coded, straight-chain aliphatic amino acids of increasing chain length. The hydrophobicity of residue 26 also correlated with the ability of the analogs to bind immobilized wild type HNP1 and to undergo further self-association. Thus, the hydrophobicity of residue 26 is not only a key determinant of the direct interactions of HNP1 with target molecules, but it also governs the ability of this peptide to form dimers and more complex quaternary structures at micromolar concentrations. Although all defensin peptides are cationic, their amphipathicity is at least as important as their positive charge in enabling them to participate in innate host defense.

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Section: Discussionmentioning

confidence: 99%

Trp-26 Imparts Functional Versatility to Human α-Defensin HNP1

Wei

Pazgier

Leeuw

et al. 2010

Journal of Biological Chemistry

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“…They are thought to play important roles in maintenance of normal cellular and physiological processes of animals (Magert et al, 2002;Kreutzmann et al, 2004) and pathogenesis of mammalian parasitic apicomplexans (Pszenny et al, 2000(Pszenny et al, , 2002Morris et al, 2004). As a result of exhaustive biochemical structure function analyses of the third domain of turkey ovomucoid protein conducted by the late Michael Laskowski Jr. and collaborators Lu et al, 1997Lu et al, , 2001, much is known about the relationship between domain sequence and inhibition specificity in Kazal protein-Ser protease interactions. This work culminated in the development of an additivity-based sequence to reactivity algorithm, referred from here on as the Laskowski algorithm, that predicts the inhibition constants (K i ) between Kazal domains and a set of six Ser proteases based solely on the sequence of the inhibitors (Lu et al, 2001).…”

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confidence: 99%

“…The Kazal family (MEROPS family I1, http://merops.sanger.ac.uk) was named after L. Kazal, who discovered the pancreatic secretory trypsin inhibitor PSTI (Lu et al, 2001). Besides oomycetes, Ser protease inhibitors of the Kazal family are widely distributed in animals and apicomplexans.…”

mentioning

confidence: 99%

“…As a result of exhaustive biochemical structure function analyses of the third domain of turkey ovomucoid protein conducted by the late Michael Laskowski Jr. and collaborators Lu et al, 1997Lu et al, , 2001, much is known about the relationship between domain sequence and inhibition specificity in Kazal protein-Ser protease interactions. This work culminated in the development of an additivity-based sequence to reactivity algorithm, referred from here on as the Laskowski algorithm, that predicts the inhibition constants (K i ) between Kazal domains and a set of six Ser proteases based solely on the sequence of the inhibitors (Lu et al, 2001). For each Kazal domain, there are 12 contact positions (P6, P5, P4, P3, P2, P1, P1', P2', P3', P14', P15', and P18') responsible for the interactions between Kazal domains and the cognate Ser proteases (Read et al, 1983;Laskowski et al, 1987;Lu et al, 1997Lu et al, , 2001.…”

mentioning

confidence: 99%

“…This work culminated in the development of an additivity-based sequence to reactivity algorithm, referred from here on as the Laskowski algorithm, that predicts the inhibition constants (K i ) between Kazal domains and a set of six Ser proteases based solely on the sequence of the inhibitors (Lu et al, 2001). For each Kazal domain, there are 12 contact positions (P6, P5, P4, P3, P2, P1, P1', P2', P3', P14', P15', and P18') responsible for the interactions between Kazal domains and the cognate Ser proteases (Read et al, 1983;Laskowski et al, 1987;Lu et al, 1997Lu et al, , 2001. Changes in noncontact residues typically do not affect equilibrium constants (K a , the reciprocal of K i ), whereas changes in contact residues cause significant alterations of K a (Lu et al, 2001).…”

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confidence: 99%

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A Second Kazal-Like Protease Inhibitor from Phytophthora infestans Inhibits and Interacts with the Apoplastic Pathogenesis-Related Protease P69B of Tomato

2005

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The plant apoplast forms a protease-rich environment in which proteases are integral components of the plant defense response. Plant pathogenic oomycetes, such as the potato (Solanum tuberosum) and tomato (Lycopersicon esculentum) pathogen Phytophthora infestans, secrete a diverse family of serine protease inhibitors of the Kazal family. Among these, the two-domain EPI1 protein was shown to inhibit and interact with the pathogenesis-related protein P69B subtilase of tomato and was implicated in counter-defense. Here, we describe and functionally characterize a second extracellular protease inhibitor, EPI10, from P. infestans. EPI10 contains three Kazal-like domains, one of which was predicted to be an efficient inhibitor of subtilisin A by an additivity-based sequence to reactivity algorithm (Laskowski algorithm). The epi10 gene was up-regulated during infection of tomato, suggesting a potential role during pathogenesis. Recombinant EPI10 specifically inhibited subtilisin A among the major serine proteases, and inhibited and interacted with P69B subtilase of tomato. The finding that P. infestans evolved two distinct and structurally divergent protease inhibitors to target the same plant protease suggests that inhibition of P69B could be an important infection mechanism for this pathogen.The plant apoplast forms a protease-rich environment in which proteases are integral components of the plant defense response (Tornero et al., 1997;Jorda et al., 1999;van Loon and van Strien, 1999;Kruger et al., 2002;Xia et al., 2004). For example, the subtilisin-like Ser protease P69B, an apoplastic pathogenesis-related (PR) protein of tomato (Lycopersicon esculentum), has long been tied to plant defense (Tornero et al., 1997;Zhao et al., 2003;Tian et al., 2004). P69B is induced by multiple plant pathogens, including the oomycete Phytophthora infestans, citrus exocortis viroid, and the bacterium Pseudomonas syringae (Tornero et al., 1997;Zhao et al., 2003;Tian et al., 2004), and appears to account for a significant portion of the increase in total endoprotease activity observed in defense-activated tomato (Tornero et al., 1997;Zhao et al., 2003;Tian et al., 2004). Rcr3, an apoplastic papain-like Cys protease from tomato, is required for specific resistance to the plant pathogenic fungus Cladosporium fulvum (Kruger et al., 2002). In Arabidopsis (Arabidopsis thaliana), the extracellular aspartic protease CDR1 functions in disease resistance signaling as a positive regulator of cell death (Xia et al., 2004). These findings suggest that suppression of plant protease-mediated host defenses could be one of the diverse strategies that plant pathogens have evolved to survive in the plant intercellular space and colonize plant tissue. Indeed, our laboratory recently reported that plant pathogenic oomycetes secrete a diverse family of Kazal-like Ser protease inhibitors with at least 35 members identified from P. infestans, Phytophthora sojae, Phytophthora ramorum, Phytophthora brassicae, and the downy mildew Plasmopara halstedii (Tian et ...

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Theoretical analysis of adsorption thermodynamics for hydrophobic peptide residues on SAM surfaces of varying functionality

Latour

Rini

2002

J. Biomed. Mater. Res.

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At a fundamental level, protein adsorption to a synthetic surface must be strongly influenced by the interaction between the peptide residues presented by the protein's surface (primary protein structure) and the functional groups presented by the synthetic surface. In this study, semi-empirical molecular modeling was used along with experimental wetting data to theoretically approach protein adsorption at this primary structural level. Changes in enthalpy, entropy, and Gibbs free energy were calculated as a function of residue-surface separation distance for the adsorption of individual hydrophobic peptide residues (valine, leucine, phenylalanine) on alkanethiol self-assembled monolayers on gold [Au-S(CH(2))(15)-X; X = CH(3), OH, NH(3)(+), COO(-)]. The results predict that the adsorption of each type of hydrophobic residue is energetically favorable and entropy dominated on a methyl-terminated hydrophobic surface, energetically unfavorable and enthalpy dominated on a hydroxyl-terminated neutral hydrophilic surface, and very slightly favorable to unfavorable and enthalpy dominated on charged surfaces. These theoretical results provide a basis for understanding some of the fundamental effects governing protein adsorption to synthetic surfaces. This level of understanding is needed for the proactive design of surfaces to control protein adsorption and subsequent cellular response for both implant and tissue engineering applications.

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Predicting the reactivity of proteins from their sequence alone: Kazal family of protein inhibitors of serine proteinases

Cited by 82 publications

References 47 publications

Trp-26 Imparts Functional Versatility to Human α-Defensin HNP1

Trp-26 Imparts Functional Versatility to Human α-Defensin HNP1

A Second Kazal-Like Protease Inhibitor from Phytophthora infestans Inhibits and Interacts with the Apoplastic Pathogenesis-Related Protease P69B of Tomato

Theoretical analysis of adsorption thermodynamics for hydrophobic peptide residues on SAM surfaces of varying functionality

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