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Int. J. Mol. Sci. 2017, 18(5), 1087; doi:10.3390/ijms18051087

The Lys-Asp-Tyr Triad within the Mite Allergen Der p 1 Propeptide Is a Critical Structural Element for the pH-Dependent Initiation of the Protease Maturation

1
Macromolécules Biologiques, Centre for Protein Engineering, University of Liège, B-4000 Liège, Belgium
2
Department of Infection and Immunity, Luxembourg Institute of Health (LIH), L-4354 Esch-sur-Alzette, Luxembourg
3
NMR and Structure Analysis Unit, Department of Organic Chemistry, Ghent University, B-9000 Ghent, Belgium
4
Laboratoire d’Enzymologie, Centre for Protein Engineering, University of Liège, B-4000 Liège, Belgium
5
Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
*
Author to whom correspondence should be addressed.
Academic Editors: Fatima Ferreira and Terrence Piva
Received: 8 February 2017 / Revised: 10 May 2017 / Accepted: 12 May 2017 / Published: 20 May 2017
(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)
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Abstract

The major house dust mite allergen, Der p 1, is a papain-like cysteine protease expressed as an inactive precursor, proDer p 1, carrying an N-terminal propeptide with a unique structure. The maturation of the zymogen into an enzymatically-active form of Der p 1 is a multistep autocatalytic process initiated under acidic conditions through conformational changes of the propeptide, leading to the loss of its inhibitory ability and its subsequent gradual cleavage. The aims of this study were to characterize the residues present in the Der p 1 propeptide involved in the initiation of the zymogen maturation process, but also to assess the impact of acidic pH on the propeptide structure, the activity of Der p 1 and the fate of the propeptide. Using various complementary enzymatic and structural approaches, we demonstrated that a structural triad K17p-D51p-Y19p within the N-terminal domain of the propeptide is essential for its stabilization and the sensing of pH changes. Particularly, the protonation of D51p under acidic conditions unfolds the propeptide through disruption of the K17p-D51p salt bridge, reduces its inhibition capacity and unmasks the buried residues K17p and Y19p constituting the first maturation cleavage site of the zymogen. Our results also evidenced that this triad acts in a cooperative manner with other propeptide pH-responsive elements, including residues E56p and E80p, to promote the propeptide unfolding and/or to facilitate its proteolysis. Furthermore, we showed that acidic conditions modify Der p 1 proteolytic specificity and confirmed that the formation of the first intermediate represents the limiting step of the in vitro Der p 1 maturation process. Altogether, our results provide new insights into the early events of the mechanism of proDer p 1 maturation and identify a unique structural triad acting as a stabilizing and a pH-sensing regulatory element. View Full-Text
Keywords: cysteine protease; Der p 1; pH sensor; pH unfolding; propeptide; maturation cysteine protease; Der p 1; pH sensor; pH unfolding; propeptide; maturation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Chevigné, A.; Campizi, V.; Szpakowska, M.; Bourry, D.; Dumez, M.-E.; Martins, J.C.; Matagne, A.; Galleni, M.; Jacquet, A. The Lys-Asp-Tyr Triad within the Mite Allergen Der p 1 Propeptide Is a Critical Structural Element for the pH-Dependent Initiation of the Protease Maturation. Int. J. Mol. Sci. 2017, 18, 1087.

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