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Int. J. Mol. Sci. 2017, 18(7), 1373; doi:10.3390/ijms18071373

Profiling the Extended Cleavage Specificity of the House Dust Mite Protease Allergens Der p 1, Der p 3 and Der p 6 for the Prediction of New Cell Surface Protein Substrates

1
Faculty of Medicine, Division of Research Affairs, Chulalongkorn University, 10330 Bangkok, Thailand
2
Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29, rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg
3
Laboratoire des Macromolécules Biologiques, Centre for Protein Engineering (CIP), University of Liège, 4000 Liège, Belgium
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 15 May 2017 / Revised: 16 June 2017 / Accepted: 21 June 2017 / Published: 27 June 2017
(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)
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Abstract

House dust mite (HDM) protease allergens, through cleavages of critical surface proteins, drastically influence the initiation of the Th2 type immune responses. However, few human protein substrates for HDM proteases have been identified so far, mainly by applying time-consuming target-specific individual studies. Therefore, the identification of substrate repertoires for HDM proteases would represent an unprecedented key step toward a better understanding of the mechanism of HDM allergic response. In this study, phage display screenings using totally or partially randomized nonameric peptide substrate libraries were performed to characterize the extended substrate specificities (P5–P4′) of the HDM proteases Der p 1, Der p 3 and Der p 6. The bioinformatics interface PoPS (Prediction of Protease Specificity) was then applied to define the proteolytic specificity profile of each protease and to predict new protein substrates within the human cell surface proteome, with a special focus on immune receptors. Specificity profiling showed that the nature of residues in P1 but also downstream the cleavage sites (P′ positions) are important for effective cleavages by all three HDM proteases. Strikingly, Der p 1 and Der p 3 display partially overlapping specificities. Analysis with PoPS interface predicted 50 new targets for the HDM proteases, including 21 cell surface receptors whose extracellular domains are potentially cleaved by Der p 1, Der p 3 and/or Der p 6. Twelve protein substrate candidates were confirmed by phage ELISA (enzyme linked immunosorbent assay). This extensive study of the natural protein substrate specificities of the HDM protease allergens unveils new cell surface target receptors for a better understanding on the role of these proteases in the HDM allergic response and paves the way for the design of specific protease inhibitors for future anti-allergic treatments. View Full-Text
Keywords: house dust mite; Dermatophagoides pteronyssinus; allergen; protease; phage display; cell surface proteome; phage substrate house dust mite; Dermatophagoides pteronyssinus; allergen; protease; phage display; cell surface proteome; phage substrate
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MDPI and ACS Style

Jacquet, A.; Campisi, V.; Szpakowska, M.; Dumez, M.-E.; Galleni, M.; Chevigné, A. Profiling the Extended Cleavage Specificity of the House Dust Mite Protease Allergens Der p 1, Der p 3 and Der p 6 for the Prediction of New Cell Surface Protein Substrates. Int. J. Mol. Sci. 2017, 18, 1373.

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