The Squamous Cell Carcinoma Antigen 2 Inhibits the Cysteine Proteinase Activity of a Major Mite Allergen, Der p 1

Abstract

The squamous cell carcinoma antigens 1 (SCCA1) and SCCA2 belong to the ovalbumin-serpin family. Although SCCA1 and SCCA2 are closely homologous, these two molecules have distinct properties; SCCA1 inhibits cysteine proteinases such as cathepsin K, L, and S, whereas SCCA2 inhibits serine proteinases such as cathepsin G and human mast cell chymase. Although several intrinsic target proteinases for SCCA1 and SCCA2 have been found, the biological roles of SCCA1 and SCCA2 remain unknown. A mite allergen, Der p 1, is one of the most immunodominant allergens and also acts as a cysteine proteinase probably involved in the pathogenesis of allergic diseases. We have recently shown that both SCCA1 and SCCA2 are induced by two related Th2-type cytokines, IL-4 and IL-13, in bronchial epithelial cells and that SCCA expression is augmented in bronchial asthma patients. In this study, we explored the possibility that SCCA proteins target Der p 1, and it turned out that SCCA2, but not SCCA1, inhibited the catalytic activities of Der p 1. We furthermore analyzed the inhibitory mechanism of SCCA2 on Der p 1. SCCA2 contributed the suicide substrate-like mechanism without formation of a covalent complex, causing irreversible impairment of the catalytic activity of Der p 1, as SCCA1 does on papain. In addition, resistance to cleavage by Der p 1 also contributed to the inhibitory mechanism of SCCA2. These results suggest that SCCA2 acts as a cross-class serpin targeting an extrinsic cysteine proteinase derived from house dust mites and that it may have a protective role against biological reactions caused by mites. The squamous cell carcinoma antigens 1 (SCCA1) and SCCA2 belong to the ovalbumin-serpin family. Although SCCA1 and SCCA2 are closely homologous, these two molecules have distinct properties; SCCA1 inhibits cysteine proteinases such as cathepsin K, L, and S, whereas SCCA2 inhibits serine proteinases such as cathepsin G and human mast cell chymase. Although several intrinsic target proteinases for SCCA1 and SCCA2 have been found, the biological roles of SCCA1 and SCCA2 remain unknown. A mite allergen, Der p 1, is one of the most immunodominant allergens and also acts as a cysteine proteinase probably involved in the pathogenesis of allergic diseases. We have recently shown that both SCCA1 and SCCA2 are induced by two related Th2-type cytokines, IL-4 and IL-13, in bronchial epithelial cells and that SCCA expression is augmented in bronchial asthma patients. In this study, we explored the possibility that SCCA proteins target Der p 1, and it turned out that SCCA2, but not SCCA1, inhibited the catalytic activities of Der p 1. We furthermore analyzed the inhibitory mechanism of SCCA2 on Der p 1. SCCA2 contributed the suicide substrate-like mechanism without formation of a covalent complex, causing irreversible impairment of the catalytic activity of Der p 1, as SCCA1 does on papain. In addition, resistance to cleavage by Der p 1 also contributed to the inhibitory mechanism of SCCA2. These results suggest that SCCA2 acts as a cross-class serpin targeting an extrinsic cysteine proteinase derived from house dust mites and that it may have a protective role against biological reactions caused by mites. The squamous cell carcinoma antigens 1 (SCCA1: SERPINB3) 1The abbreviations used are: SCCAsquamous cell carcinoma antigenRSLreactive site loopCrmAcytokine response modifier A, PI9, proteinase inhibitor 9PAR-2protease-activated receptor 2MALDI-TOFmatrix-associated laser desorption ionization time-of-flightPEO-Mpolyethylene oxide-maleimide.1The abbreviations used are: SCCAsquamous cell carcinoma antigenRSLreactive site loopCrmAcytokine response modifier A, PI9, proteinase inhibitor 9PAR-2protease-activated receptor 2MALDI-TOFmatrix-associated laser desorption ionization time-of-flightPEO-Mpolyethylene oxide-maleimide. and SCCA2 (SERPINB4) belong to the ovalbuminserpin (serine proteinase inhibitors) family and are 91% identical at the amino acid level (1Schick C. Kamachi Y. Bartuski A.J. Cataltepe S. Schechter N.M. Pemberton P.A. Silverman G.A. J. Biol. Chem. 1997; 272: 1849-1855Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). Both genes locate at 18q21.3 very closely, suggesting that either gene could arise from the other by gene duplication (2Schneider S.S. Schick C. Fish K.E. Miller E. Pena J.C. Treter S.D. Hui S.M. Silverman G.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 3147-3151Crossref PubMed Scopus (250) Google Scholar). SCCA1 was originally purified from squamous cell carcinoma of uterine cervix (3Kato H. Torigoe T. Cancer. 1977; 40: 1621-1628Crossref PubMed Scopus (595) Google Scholar), and it turned out that SCCA1 and SCCA2 are co-expressed broadly in normal tissues: the epithelium of tongue, tonsil, esophagus, uterine cervix, vagina, and the conducting airways; Hassall's corpuscles of the thymus; and some areas of the skin (4Cataltepe S. Gornstein E.R. Schick C. Kamachi Y. Chatson K. Fries J. Silverman G.A. Upton M.P. J. Histochem. Cytochem. 2000; 48: 113-122Crossref PubMed Scopus (133) Google Scholar). Although SCCA1 and SCCA2 are very homologous, these two molecules have distinct properties; SCCA1 inhibits cysteine proteinases such as cathepsin K, L, S, and papain, whereas SCCA2 inhibits serine proteinases such as cathepsin G and human mast cell chymase (1Schick C. Kamachi Y. Bartuski A.J. Cataltepe S. Schechter N.M. Pemberton P.A. Silverman G.A. J. Biol. Chem. 1997; 272: 1849-1855Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 5Takeda A. Yamamoto T. Nakamura Y. Takahashi T. Hibino T. FEBS Lett. 1995; 359: 78-80Crossref PubMed Scopus (61) Google Scholar, 6Schick C. Pemberton P.A. Shi G.P. Kamachi Y. Cataltepe S. Bartuski A.J. Gornstein E.R. Bromme D. Chapman H.A. Silverman G.A. Biochemistry. 1998; 37: 5258-5266Crossref PubMed Scopus (253) Google Scholar). The specificities of SCCA1 and SCCA2 are due to the difference in the reactive site loop (RSL) sequences because only 7 amino acid residues among 13 (54%) were identical in the RSL regions (P7 to P6′) of these proteins (7Luke C. Schick C. Tsu C. Whisstock J.C. Irving J.A. Bromme D. Juliano L. Shi G.P. Chapman H.A. Silverman G.A. Biochemistry. 2000; 39: 7081-7091Crossref PubMed Scopus (49) Google Scholar). Although target proteinases for most serpins are the chymotrypsin family, the serpin inhibiting cysteine proteinases is defined as a cross-class inhibitor. Cytokine response modifier A (CrmA) derived from cowpox virus and proteinase inhibitor 9 (PI9, SERPINB9) inhibits both a serine proteinase (granzyme B) and a cysteine proteinase (caspase proteins) (8Annand R.R. Dahlen J.R. Sprecher C.A. De Dreu P. Foster D.C. Mankovich J.A. Talanian R.V. Kisiel W. Giegel D.A. Biochem. J. 1999; 342: 655-665Crossref PubMed Scopus (97) Google Scholar, 9Bird C.H. Sutton V.R. Sun J. Hirst C.E. Novak A. Kumar S. Trapani J.A. Bird P.I. Mol. Cell. Biol. 1998; 18: 6387-6398Crossref PubMed Scopus (254) Google Scholar, 10Komiyama T. Ray C.A. Pickup D.J. Howard A.D. Thornberry N.A. Peterson E.P. Salvesen G. J. Biol. Chem. 1994; 269: 19331-19337Abstract Full Text PDF PubMed Google Scholar, 11Quan L.T. Caputo A. Bleackley R.C. Pickup D.J. Salvesen G.S. J. Biol. Chem. 1995; 270: 10377-10379Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar). So thus far, SCCA1, CrmA, and PI9 are all obvious cross-class serpins (12Silverman G.A. Bird P.I. Carrell R.W. Church F.C. Coughlin P.B. Gettins P.G. Irving J.A. Lomas D.A. Luke C.J. Moyer R.W. Pemberton P.A. Remold-O'Donnell E. Salvesen G.S. Travis J. Whisstock J.C. J. Biol. Chem. 2001; 276: 33293-33296Abstract Full Text Full Text PDF PubMed Scopus (1060) Google Scholar). Although several intrinsic target proteinases for SCCA1 and SCCA2 have been found, the biological roles of SCCA1 and SCCA2 remain unknown. We have recently shown that expression of both SCCA1 and SCCA2 is up-regulated by two related Th2-type cytokines, IL-4 and IL-13, in bronchial epithelial cells and that SCCA expression is augmented in bronchial lesions and in peripheral blood of bronchial asthma patients (13Yuyama N. Davies D.E. Akaiwa M. Matsui K. Hamasaki Y. Suminami Y. Lu Yoshida N. Maeda M. Pandit A. Lordan J.L. Kamogawa Y. Arima K. Nagumo F. Sugimachi M. Berger A. Richards I. Roberds S.L. Yamashita T. Kishi F. Kato H. Arai K. Ohshima K. Tadano J. Hamasaki N. Miyatake S. Sugita Y. Holgate S.T. Izuhara K. Cytokine. 2002; 19: 287-296Crossref PubMed Scopus (174) Google Scholar). It is well known that IL-4 and IL-13 are involved in the pathogenesis of bronchial asthma (14Wills-Karp M. J. Allergy Clin. Immunol. 2001; 107: 9-18Abstract Full Text PDF PubMed Scopus (208) Google Scholar, 15Izuhara K. Umeshita-Suyama R. Akaiwa M. Shirakawa T. Deichmann K.A. Arima K. Hamasaki N. Hopkin J.M. Arch. Immunol. Ther. Exp. 2000; 48: 505-512PubMed Google Scholar), predominantly expressed in the lesions of asthma patients (16Robinson D.S. Hamid Q. Ying S. Tsicopoulos A. Barkans J. Bentley A.M. Corrigan C. Durham S.R. Kay A.B. N. Engl. J. Med. 1992; 326: 298-304Crossref PubMed Scopus (2560) Google Scholar, 17Kotsimbos T.C. Ernst P. Hamid Q.A. Proc. Assoc. Am. Physicians. 1996; 108: 368-373PubMed Google Scholar, 18Humbert M. Durham S.R. Kimmitt P. Powell N. Assoufi B. Pfister R. Menz G. Kay A.B. Corrigan C.J. J. Allergy Clin. Immunol. 1997; 99: 657-665Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar). These findings raise the possibility that SCCA1 and SCCA2 may perform their activities in the lesions of bronchial asthma. squamous cell carcinoma antigen reactive site loop cytokine response modifier A, PI9, proteinase inhibitor 9 protease-activated receptor 2 matrix-associated laser desorption ionization time-of-flight polyethylene oxide-maleimide. squamous cell carcinoma antigen reactive site loop cytokine response modifier A, PI9, proteinase inhibitor 9 protease-activated receptor 2 matrix-associated laser desorption ionization time-of-flight polyethylene oxide-maleimide. Der p 1 and Der f 1, group I allergens derived from house dust mites, Dermatophagoides pteronyssinus and Dermatophagoides farinae, respectively, are major components of mites and their is closely of bronchial and allergic Chapman J. Allergy Clin. Immunol. Full Text PDF PubMed Scopus Google Scholar, R. Holgate S.T. N. Engl. J. Med. PubMed Scopus Google Scholar, J. Immunol. Google Scholar, S. J. Allergy Clin. Immunol. Full Text PDF PubMed Scopus Google Scholar). It been that of and of in allergic patients are p 1 that Der p 1 is one of the most immunodominant allergens Chapman J. Allergy Clin. Immunol. Full Text PDF PubMed Scopus Google Scholar, J. Immunol. Google Scholar). Der p 1 is a cysteine amino acid amino and the catalytic as other cysteine proteinases F. H. Immunol. 1998; 19: Full Text Full Text PDF PubMed Scopus Google Scholar). The of Der p 1 been on the of papain, suggesting that Der p 1 is of two by a the site the catalytic N. C.J. N.A. 1994; PubMed Scopus Google Scholar). It been that Der p 1 several proteins such as H. C. E.R. D.C. G.A. C. J. Clin. 1999; PubMed Scopus Google Scholar), protease-activated receptor 2 N. D.J. A.J. K.A. G.A. J. Immunol. 2002; PubMed Scopus Google Scholar), J. Exp. Med. 1995; PubMed Scopus Google Scholar), F. J. Exp. Med. 1998; PubMed Scopus Google Scholar), and A.M. L. F. Clin. Exp. 2002; PubMed Scopus Google in Although the role of the catalytic activity of Der p 1 in not been the results that the catalytic activity of Der p 1 for the pathogenesis of bronchial in to Der p 1 by the of the bronchial epithelial H. C. E.R. D.C. G.A. C. J. Clin. 1999; PubMed Scopus Google Scholar). Der p 1 of such as and in bronchial epithelial cells by N. D.J. A.J. K.A. G.A. J. Immunol. 2002; PubMed Scopus Google Scholar, Sun G. G. M. A. S. Biochem. 1997; PubMed Scopus Google Scholar, C. S. G.A. J. Immunol. 1998; Google Scholar). Der p 1 the by on cells F. J. Exp. Med. 1998; PubMed Scopus Google on cells A.M. L. F. Clin. Exp. 2002; PubMed Scopus Google Scholar). We that SCCA proteins induced by IL-4 and IL-13 target extrinsic proteinases derived from house mites in the lesions of bronchial asthma. this we SCCA1 and SCCA2 the catalytic activities of group I mite allergens in this It turned out that SCCA2 inhibited the catalytic activities of both Der p 1 and Der f 1 and that SCCA2 inhibitory activity by the catalytic activity of Der p 1 and by to the cleavage by Der p 1. These results suggest that SCCA2 acts as a cross-class serpin targeting extrinsic cysteine Der p 1 and Der f 1, and that SCCA2 may have a protective role against biological cathepsin cathepsin L, and human mast cell chymase were from and of and and were as K. Y. Arima K. I. Izuhara K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). SCCA2 were by two was the SCCA2 as a and a of were The of SCCA1 and SCCA2 were by and the site of SCCA1 and SCCA2 proteins were expressed in an and by of the proteins was as by of an of the proteins were by of the Der p 1 and Der f 1 Der p 1 and Der f 1 proteins were as T. T. T. H. Y. Clin. Exp. 2001; PubMed Scopus Google Scholar, T. R. T. M. H. K. K. H. FEBS Lett. 2002; PubMed Scopus Google Scholar). of house dust mite group 1 Der p Der p Der f and Der f were the of cells of and to the by against an The were purified The was as by The was by Der p and Der f were used for most of Der p 1 and Der f 1 were as T. T. T. H. Y. Clin. Exp. 2001; PubMed Scopus Google Scholar, F. Mol. 1998; PubMed Scopus Google Scholar). The used for was from The of Der p 1 Der f 1 2 for at were the of SCCA proteins for at in 1 2 and of to the the activity was by and of and of of cleavage of were as F. J. Exp. Med. 1998; PubMed Scopus Google Scholar). A human cell cell was and 1 for in by Der p 1 2 was 1 SCCA proteins for at cleavage was by cells the of Der p 1 and SCCA proteins the of Der p 1 and SCCA proteins and respectively, for 2 at of on cell was analyzed by and in the was in the by of a Der p 1 and SCCA proteins were in for 2 at and the reactive were to of the SCCA and Der p 2 Der p 1 and SCCA proteins were in for at the was to the the were and was to the The were The of the proteins on the were by of the of Der p Der p 1 was for 2 at The were to and to The were used for were and all from The were in and of SCCA1 and perform of SCCA1 and SCCA2, we expressed and purified proteins of SCCA1 and SCCA2. We that SCCA1 inhibited the cysteine activities of and cathepsin but not the serine activities of cathepsin G and human mast cell whereas SCCA2 the as K. Y. Arima K. I. Izuhara K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). These results that purified SCCA1 and SCCA2 proteins were of of Der p 1 and Der f 1 by analyzed SCCA1 SCCA2 inhibited catalytic activities of Der p 1 and Der f 1. The and of Der p 1 used in the were as and irreversible inhibitor for cysteine only of at a at Der p 1 Der f 1 site of Der p 1 Der f 1 was we analyzed of SCCA1 and SCCA2 on the catalytic activity of Der p 1 and Der f 1. the of Der p 1 Der f 1 was at SCCA2 inhibited catalytic activities of both Der p 1 and Der f 1 in a whereas SCCA1 only at The inhibitory of SCCA2 were of of Der p 1 and Der f 1 not the of Der p 1 and SCCA1 SCCA2 was at the inhibitory of SCCA2 of the at 1 SCCA1 a inhibitory SCCA2. inhibitory These results that SCCA2, and to a SCCA1, Der p 1 and that SCCA2 is a cross-class serpin that both serine and cysteine proteinases as well as CrmA, PI9, and of and for and Der p difference at p difference at p in a of SCCA on by Der p SCCA2 inhibitory on Der p 1, Der p 1 not only the but also an as a we analyzed the inhibitory of SCCA proteins on cleavage by Der p 1. of Der p 1 cells caused the cleavage of The of SCCA2 expression of and SCCA1 to some of the in the was in the cleavage of on cells These results that SCCA2 also inhibitory on the of Der p 1 of the in SCCA1 and SCCA2 by Der p the cleavage in of SCCA1 and SCCA2 by Der p 1, of Der p in SCCA1 by the of to the from and to the whereas the SCCA2 only one to the from to the These results that Der p 1 SCCA2 a as other serpins In the Der p 1 and SCCA1 not and Der p 1 the RSL of of SCCA2 Der p it is well known that a serpin and target proteinase an by an for J.A. Carrell R.W. 2000; PubMed Scopus Google Scholar), we have recently that SCCA1 inhibited the catalytic activity of without a covalent K. Y. Arima K. I. Izuhara K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We analyzed the of SCCA2 and Der p 1. the SCCA2 and Der p 1, we a We used a of Der p 1 and SCCA2 in the catalytic activity of Der p 1 was SCCA2 and Der p 1 were to their These results that SCCA2 Der p 1 by as well as the SCCA1 and papain. of Der p 1 by SCCA2 SCCA2 inhibited the catalytic activity of Der p 1 without a the of the SCCA2 and Der p 1, we analyzed the catalytic activity of the Der p 1 by the Although the catalytic activity of Der p 1 was inhibited in the 2 Der p 1 and SCCA2, was to the it turned out that the catalytic activity of Der p 1 but the The of Der p 1 was that of Der p 1 p the impairment of the catalytic These results the possibility that SCCA2 caused a of Der p 1, catalytic this we of Der p 1 by a cysteine of Der p 1 by was the level of Der p 1 These results suggest that of the catalytic activity of Der p 1 may due to we the possibility that the cysteine of the was by SCCA2. of SCCA2 against by Der p the irreversible of Der p 1 contributed to the mechanism of SCCA2, it could not it because Der p 1 catalytic activity at the level only serpin inhibitory activity in the suicide substrate-like it that the difference of to cleavage by the target proteinase could the inhibitory activity of this we analyzed the of SCCA2 in the of It turned out that SCCA2 was to by Der p 1 SCCA1 and that of SCCA2 of SCCA1 was papain, SCCA1 to and was These results that resistance against the cleavage by the target proteinase was a of SCCA2, and it could at SCCA2 inhibitory activity on Der p 1 of in the RSL of SCCA2 and SCCA1 for on Der p distinct of SCCA1 and SCCA2 the inhibitory on Der p 1 are to due to the difference of their RSL the RSL of SCCA1 for that of SCCA2, that the inhibitory on Der p 1 was on the RSL of SCCA2 SCCA1 SCCA2 We amino acid for the RSL of SCCA2 that to SCCA1 and analyzed inhibitory on Der p 1 was respectively, all of the the inhibitory SCCA2 SCCA2 that these residues were both and were and respectively, the inhibitory was augmented SCCA2 SCCA2 and were all and respectively, the inhibitory was up-regulated A and SCCA2 Although was of the inhibitory was SCCA2 SCCA2 that of the of for of the inhibitory as of of SCCA not the in SCCA2 not but of from SCCA2 we that of the RSL of SCCA for that of SCCA1 the of the amino acid of the RSL not of of SCCA proteins and their inhibitory site amino acid as the amino acid as SCCA2. in a the of the amino acid of the RSL in SCCA2 we to the of SCCA1, SCCA2, and SCCA2 and analyzed their inhibitory the to SCCA2 but not the to SCCA1 and SCCA2, inhibited the catalytic activity of Der p 1 the role of the of the RSL in SCCA of SCCA2 the of SCCA2 and SCCA2 It turned out that the of SCCA2 were the as SCCA2. It the cleavage of by Der p 1 not It was by Der p 1 and not It not a covalent Der p 1 not SCCA2 caused irreversible on the catalytic activity of Der p 1 and of to the level as SCCA2 SCCA2 was to cleavage by Der p 1 SCCA2 at at These results that the difference of resistance against cleavage by Der p 1 contributed to the inhibitory activities of SCCA2 and SCCA2 In this study, we that SCCA2 inhibited the cysteine proteinase activity of group I mite Der p 1 and Der f 1. Although it been that SCCA2 only serine SCCA2 inhibits both serine and cysteine proteinases to the cross-class serpin family, as well as CrmA, PI9, and It been that Der p 1 biological activities allergic reactions such as of by H. C. E.R. D.C. G.A. C. J. Clin. 1999; PubMed Scopus Google Scholar), of in bronchial epithelial cells by N. D.J. A.J. K.A. G.A. J. Immunol. 2002; PubMed Scopus Google Scholar, Sun G. G. M. A. S. Biochem. 1997; PubMed Scopus Google Scholar, C. S. G.A. J. Immunol. 1998; Google Scholar), and of by F. J. Exp. Med. 1998; PubMed Scopus Google Scholar, A.M. L. F. Clin. Exp. 2002; PubMed Scopus Google in Although the role of the catalytic activity of Der p 1 in it is that the cysteine proteinase activity of Der p 1 acts as a a of bronchial on the in this were the SCCA2 a protective role against group I mite allergens in the lesions of bronchial IL-4 and IL-13, expression of SCCA2 in bronchial epithelial are known to involved in the pathogenesis of bronchial asthma (14Wills-Karp M. J. Allergy Clin. Immunol. 2001; 107: 9-18Abstract Full Text PDF PubMed Scopus (208) Google Scholar, 15Izuhara K. Umeshita-Suyama R. Akaiwa M. Shirakawa T. Deichmann K.A. Arima K. Hamasaki N. Hopkin J.M. Arch. Immunol. Ther. Exp. 2000; 48: 505-512PubMed Google Scholar). The SCCA2 and group I mite allergens may the of bronchial asthma. SCCA proteins a protective role against cysteine proteinases derived from because it is known that some cysteine proteinases derived from J.C. R. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google and that against J. Allergy Clin. Immunol. 2001; 107: Full Text Full Text PDF PubMed Scopus Google Scholar). We the inhibitory mechanism of SCCA2 on Der p 1, and the SCCA2 was at the site in RSL SCCA2 and Der p 1 not a a covalent SCCA2 the catalytic activity of Der p 1, probably by irreversible and The serpins a suicide substrate-like inhibitory mechanism in the RSL of the serpin is by the and a that the normal of the proteinase is by the serine of the proteinase (12Silverman G.A. Bird P.I. Carrell R.W. Church F.C. Coughlin P.B. Gettins P.G. Irving J.A. Lomas D.A. Luke C.J. Moyer R.W. Pemberton P.A. Remold-O'Donnell E. Salvesen G.S. Travis J. Whisstock J.C. J. Biol. Chem. 2001; 276: 33293-33296Abstract Full Text Full Text PDF PubMed Scopus (1060) Google Scholar, S. Biol. 2001; PubMed Scopus Google Scholar). the a serpin an a serine proteinase by an In the of the RSL the of the the of the serpin and the it for the to J.A. Carrell R.W. 2000; PubMed Scopus Google Scholar). We have recently shown that the inhibitory mechanism of cross-class SCCA1, is among the serpin in that SCCA1 inhibitory activity in two the suicide substrate-like mechanism without formation of a covalent and causing irreversible impairment of the catalytic activity of K. Y. Arima K. I. Izuhara K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The in SCCA2 and Der p 1 that this mechanism among cross-class It is that the a cross-class serpin and target cysteine proteinase was that the not from catalytic the to the may of the target catalytic The that other cross-class and PI9, not a serine (8Annand R.R. Dahlen J.R. Sprecher C.A. De Dreu P. Foster D.C. Mankovich J.A. Talanian R.V. Kisiel W. Giegel D.A. Biochem. J. 1999; 342: 655-665Crossref PubMed Scopus (97) Google Scholar, 9Bird C.H. Sutton V.R. Sun J. Hirst C.E. Novak A. Kumar S. Trapani J.A. Bird P.I. Mol. Cell. Biol. 1998; 18: 6387-6398Crossref PubMed Scopus (254) Google Scholar, 10Komiyama T. Ray C.A. Pickup D.J. Howard A.D. Thornberry N.A. Peterson E.P. Salvesen G. J. Biol. Chem. 1994; 269: 19331-19337Abstract Full Text PDF PubMed Google Scholar, 11Quan L.T. Caputo A. Bleackley R.C. Pickup D.J. Salvesen G.S. J. Biol. Chem. 1995; 270: 10377-10379Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar), may the We also that SCCA2 was to cleavage by Der p 1 SCCA1 is a of SCCA2 to the mechanism against Der p 1, from the of SCCA1 papain. The of of amino acid that at SCCA2 for resistance against Der p 1 because SCCA2 in was was to cleavage by Der p 1, the inhibitory activity against Der p 1 and not It is that the of at Der p 1 the on the of the SCCA2 and Der p 1. In to the SCCA1 and SCCA2, by amino acid in the RSL of SCCA2, we in a very inhibitor SCCA2 The of amino acid that of in the of the RSL and the of Der p 1, the SCCA to the cleavage by Der p 1 and of the SCCA2 and SCCA2 also the that of the resistance against cleavage by Der p 1 to of the inhibitory activity of the SCCA2 Although the role of the catalytic activity of Der p 1 in the pathogenesis of allergic it is that an inhibitor against catalytic activity the to a for allergic from mite it been that a inhibitory for the catalytic activities of group I mite allergens and and induced by Der p 1 in C. M. M. Clin. Exp. 2000; PubMed Scopus Google Scholar, S. Holgate S.T. Am. J. Med. 2001; Scholar). of the p 1 a as to to a to the catalytic activity of group I mite We R. for of this We also and Kato for and