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.
Der p 1; cysteine protease; maturation; pH sensor; pH unfolding; propeptide; NMR; circular dichroism; fluorescence
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Chevigne, Andy
Campizi, Vincenzo
Szpakowska, Martyna
Bourry, David
Dumez, Marie-Eve
Martins, Jose C.
Matagne, André ; Université de Liège > Département des sciences de la vie > Enzymologie et repliement des protéines
Galleni, Moreno ; Université de Liège > Département des sciences de la vie > Macromolécules biologiques
Jacquet, Alain
Language :
English
Title :
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.
Publication date :
2017
Journal title :
International Journal of Molecular Sciences
ISSN :
1661-6596
eISSN :
1422-0067
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI), Switzerland
Thomas, W.R. Hierarchy and molecular properties of house dust mite allergens. Allergol. Int. 2015, 64, 304-311.
Chapman, M.D.; Rowntree, S.; Mitchell, E.B.; di Prisco de Fuenmajor, M.C.; Platts-Mills, T.A. Quantitative assessments of IgG and IgE antibodies to inhalant allergens in patients with atopic dermatitis. J. Allergy Clin. Immunol. 1983, 72, 27-33.
Platts-Mills, T.A.; Chapman, M.D. Dust mites: Immunology, allergic disease, and environmental control. J. Allergy Clin. Immunol. 1987, 80, 755-775.
Shakib, F.; Schulz, O.; Sewell, H. A mite subversive: Cleavage of CD23 and CD25 by Der p 1 enhances allergenicity. Immunol. Today 1998, 19, 313-316.
Wan, H.; Winton, H.L.; Soeller, C.; Tovey, E.R.; Gruenert, D.C.; Thompson, P.J.; Stewart, G.A.; Taylor, G.W.; Garrod, D.R.; Cannell, M.B. et al. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J. Clin. Investig. 1999, 104, 123-133.
Kikuchi, Y.; Takai, T.; Kuhara, T.; Ota, M.; Kato, T.; Hatanaka, H.; Ichikawa, S.; Tokura, T.; Akiba, H.; Mitsuishi, K. et al. Crucial commitment of proteolytic activity of a purified recombinant major house dust mite allergen Der p1 to sensitization toward IgE and IgG responses. J. Immunol. 2006, 177, 1609-1617.
Dumez, M.E.; Herman, J.; Campizi, V.; Galleni, M.; Jacquet, A.; Chevigne, A. Orchestration of an uncommon maturation cascade of the house dust mite protease allergen quartet. Front. Immunol. 2014, 5, 138.
Herman, J.; Thelen, N.; Smargiasso, N.; Mailleux, A.C.; Luxen, A.; Cloes, M.; de Pauw, E.; Chevigné, A.; Galleni, M.; Dumez, M.E. Der p 1 is the primary activator of Der p 3, Der p 6 and Der p 9 the proteolytic allergens produced by the house dust mite Dermatophagoides pteronyssinus. Biochim. Biophys. Acta 2014, 1840, 1117-1124.
Dumez, M.E.; Teller, N.; Mercier, F.; Tanaka, T.; Vandenberghe, I.; Vandenbranden, M.; Devreese, B.; Luxen, A.; Frère, J.M.; Matagne, A. et al. Activation mechanism of recombinant Der p 3 allergen zymogen: Contribution of cysteine protease Der p 1 and effect of propeptide glycosylation. J. Biol. Chem. 2008, 283, 30606-30617.
Gough, L.; Schulz, O.; Sewell, H.F.; Shakib, F. The cysteine protease activity of the major dust mite allergen Der p 1 selectively enhances the immunoglobulin E antibody response. J. Exp. Med. 1999, 190, 1897-1902.
Jacquet, A. The role of the house dust mite-induced innate immunity in development of allergic response. Int. Arch. Allergy Immunol. 2011, 155, 95-105.
Jacquet, A. The role of innate immunity activation in house dust mite allergy. Trends Mol. Med. 2011, 17, 604-611.
Chua, K.Y.; Stewart, G.A.; Thomas, W.R.; Simpson, R.J.; Dilworth, R.J.; Plozza, T.M.; Turner, K.J. Sequence analysis of cDNA coding for a major house dust mite allergen, Der p 1. Homology with cysteine proteases. J. Exp. Med. 1988, 167, 175-182.
Takai, T.; Kato, T.; Yasueda, H.; Okumura, K.; Ogawa, H. Analysis of the structure and allergenicity of recombinant pro- and mature Der p 1 and Der f 1: Major conformational IgE epitopes blocked by prodomains. J. Allergy Clin. Immunol. 2005, 115, 555-563.
Chevigne, A.; Barumandzadeh, R.; Groslambert, S.; Cloes, B.; Dehareng, D.; Filee, P.; Marx, J.C.; Frère, J.M.; Matagne, A.; Jacquet, A. et al. Relationship between propeptide pH unfolding and inhibitory ability during ProDer p 1 activation mechanism. J. Mol. Biol. 2007, 374, 170-185.
Huete-Perez, J.A.; Engel, J.C.; Brinen, L.S.; Mottram, J.C.; McKerrow, J.H. Protease trafficking in two primitive eukaryotes is mediated by a prodomain protein motif. J. Biol. Chem. 1999, 274, 16249-16256.
Karrer, K.M.; Peiffer, S.L.; DiTomas, M.E. Two distinct gene subfamilies within the family of cysteine protease genes. Proc. Natl. Acad. Sci. USA 1993, 90, 3063-3067.
Cygler, M.; Mort, J.S. Proregion structure of members of the papain superfamily. Mode of inhibition of enzymatic activity. Biochimie 1997, 79, 645-652.
Groves, M.R.; Coulombe, R.; Jenkins, J.; Cygler, M. Structural basis for specificity of papain-like cysteine protease proregions toward their cognate enzymes. Proteins 1998, 32, 504-514.
Groves, M.R.; Taylor, M.A.; Scott, M.; Cummings, N.J.; Pickersgill, R.W.; Jenkins, J.A. The prosequence of procaricain forms an alpha-helical domain that prevents access to the substrate-binding cleft. Structure 1996, 4, 1193-1203.
Guay, J.; Falgueyret, J.P.; Ducret, A.; Percival, M.D.; Mancini, J.A. Potency and selectivity of inhibition of cathepsin K, L and S by their respective propeptides. Eur. J. Biochem. 2000, 267, 6311-6318.
Meno, K.; Thorsted, P.B.; Ipsen, H.; Kristensen, O.; Larsen, J.N.; Spangfort, M.D.; Gajhede, M.; Lund, K. The crystal structure of recombinant proDer p 1, a major house dust mite proteolytic allergen. J. Immunol. 2005, 175, 3835-3845.
McQueney, M.S.; Amegadzie, B.Y.; D’Alessio, K.; Hanning, C.R.; McLaughlin, M.M.; McNulty, D.; Carr, S.A.; Ijames, C.; Kurdyla, J.; Jones, C.S. Autocatalytic activation of human cathepsin K. J. Biol. Chem. 1997, 272, 13955-13960.
Menard, R.; Carmona, E.; Takebe, S.; Dufour, E.; Plouffe, C.; Mason, P.; Mort, J.S. Autocatalytic processing of recombinant human procathepsin L. Contribution of both intermolecular and unimolecular events in the processing of procathepsin L in vitro. J. Biol. Chem. 1998, 273, 4478-4484.
Takai, T.; Mineki, R.; Nakazawa, T.; Takaoka, M.; Yasueda, H.; Murayama, K.; Okumura, K.; Ogawa, H. Maturation of the activities of recombinant mite allergens Der p 1 and Der f 1, and its implication in the blockade of proteolytic activity. FEBS Lett. 2002, 531, 265-272.
Jacquet, A.; Magi, M.; Petry, H.; Bollen, A. High-level expression of recombinant house dust mite allergen Der p 1 in Pichia pastoris. Clin. Exp. Allergy 2002, 32, 1048-1053.
Van Oort, E.; de Heer, P.G.; van Leeuwen, W.A.; Derksen, N.I.; Muller, M.; Huveneers, S.; Aalberse, R.C.; van Ree, R. Maturation of Pichia pastoris-derived recombinant pro-Der p 1 induced by deglycosylation and by the natural cysteine protease Der p 1 from house dust mite. Eur. J. Biochem. 2002, 269, 671-679.
Takai, T.; Mizuuchi, E.; Kikuchi, Y.; Nagamune, T.; Okumura, K.; Ogawa, H. Glycosylation of recombinant proforms of major house dust mite allergens Der p 1 and Der f 1 decelerates the speed of maturation. Int. Arch. Allergy Immunol. 2006, 139, 181-187.
McIntyre, G.F.; Godbold, G.D.; Erickson, A.H. The pH-dependent membrane association of procathepsin L is mediated by a 9-residue sequence within the propeptide. J. Biol. Chem. 1994, 269, 567-572.
Jerala, R.; Zerovnik, E.; Kidric, J.; Turk, V. pH-induced conformational transitions of the propeptide of human cathepsin L. A role for a molten globule state in zymogen activation. J. Biol. Chem. 1998, 273, 11498-11504.
Bromme, D.; Nallaseth, F.S.; Turk, B. Production and activation of recombinant papain-like cysteine proteases. Methods 2004, 32, 199-206.
Ishidoh, K.; Kominami, E. Procathepsin L degrades extracellular matrix proteins in the presence of glycosaminoglycans in vitro. Biochem. Biophys. Res. Commun. 1995, 217, 624-631.
Kihara, M.; Kakegawa, H.; Matano, Y.; Murata, E.; Tsuge, H.; Kido, H.; Katunuma, N. Chondroitin sulfate proteoglycan is a potent enhancer in the processing of procathepsin L. Biol. Chem. 2002, 383, 1925-1929.
Harris, J.; Mason, D.E.; Li, J.; Burdick, K.W.; Backes, B.J.; Chen, T.; Shipway, A.; van Heeke, G.; Gough, L.; Ghaemmaghami, A. et al. Activity profile of dust mite allergen extract using substrate libraries and functional proteomic microarrays. Chem. Biol. 2004, 11, 1361-1372.
Chevigne, A.; Dumez, M.E.; Dumoulin, M.; Matagne, A.; Jacquet, A.; Galleni, M. Comparative study of mature and zymogen mite cysteine protease stability and pH unfolding. Biochim. Biophys. Acta 2010, 1800, 937-945.
Tovey, E.R.; Baldo, B.A. Localization of antigens and allergens in thin sections of the house dust mite, Dermatophagoides pteronyssinus (Acari: Pyroglyphidae). J. Med. Entomol. 1990, 27, 368-376.
Erban, T.; Hubert, J. Determination of pH in regions of the midguts of acaridid mites. J. Insect Sci. 2010, 10, 42.
