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Title: Structural Mechanisms of Inactivation in Scabies Mite Serine Protease Paralogues

Abstract

The scabies mite (Sarcoptes scabiei) is a parasite responsible for major morbidity in disadvantaged communities and immuno-compromised patients worldwide. In addition to the physical discomfort caused by the disease, scabies infestations facilitate infection by Streptococcal species via skin lesions, resulting in a high prevalence of rheumatic fever/heart disease in affected communities. The scabies mite produces 33 proteins that are closely related to those in the dust mite group 3 allergen and belong to the S1-like protease family (chymotrypsin-like). However, all but one of these molecules contain mutations in the conserved active-site catalytic triad that are predicted to render them catalytically inactive. These molecules are thus termed scabies mite inactivated protease paralogues (SMIPPs). The precise function of SMIPPs is unclear; however, it has been suggested that these proteins might function by binding and protecting target substrates from cleavage by host immune proteases, thus preventing the host from mounting an effective immune challenge. In order to begin to understand the structural basis for SMIPP function, we solved the crystal structures of SMIPP-S-I1 and SMIPP-S-D1 at 1.85 {angstrom} and 2.0 {angstrom} resolution, respectively. Both structures adopt the characteristic serine protease fold, albeit with large structural variations over much of the molecule. In bothmore » structures, mutations in the catalytic triad together with occlusion of the S1 subsite by a conserved Tyr200 residue is predicted to block substrate ingress. Accordingly, we show that both proteases lack catalytic function. Attempts to restore function (via site-directed mutagenesis of catalytic residues as well as Tyr200) were unsuccessful. Taken together, these data suggest that SMIPPs have lost the ability to bind substrates in a classical 'canonical' fashion, and instead have evolved alternative functions in the lifecycle of the scabies mite.« less

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1005763
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Mol. Biol.; Journal Volume: 390; Journal Issue: (4) ; 07, 2009
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; CLEAVAGE; COMMUNITIES; CRYSTAL STRUCTURE; DISEASE INCIDENCE; DISEASES; DUSTS; INACTIVATION; MITES; MUTAGENESIS; MUTATIONS; PARASITES; PATIENTS; PROTEINS; RESIDUES; RESOLUTION; SERINE; SUBSTRATES; TARGETS

Citation Formats

Fischer, Katja, Langendorf, Christopher G., Irving, James A., Reynolds, Simone, Willis, Charlene, Beckham, Simone, Law, Ruby H.P., Yang, Sundy, Bashtannyk-Puhalovich, Tanya A., McGowan, Sheena, Whisstock, James C., Pike, Robert N., Kemp, David J., Buckle, Ashley M., Monash), and Queensland Inst. of Med. Rsrch.). Structural Mechanisms of Inactivation in Scabies Mite Serine Protease Paralogues. United States: N. p., 2009. Web. doi:10.1016/j.jmb.2009.04.082.
Fischer, Katja, Langendorf, Christopher G., Irving, James A., Reynolds, Simone, Willis, Charlene, Beckham, Simone, Law, Ruby H.P., Yang, Sundy, Bashtannyk-Puhalovich, Tanya A., McGowan, Sheena, Whisstock, James C., Pike, Robert N., Kemp, David J., Buckle, Ashley M., Monash), & Queensland Inst. of Med. Rsrch.). Structural Mechanisms of Inactivation in Scabies Mite Serine Protease Paralogues. United States. doi:10.1016/j.jmb.2009.04.082.
Fischer, Katja, Langendorf, Christopher G., Irving, James A., Reynolds, Simone, Willis, Charlene, Beckham, Simone, Law, Ruby H.P., Yang, Sundy, Bashtannyk-Puhalovich, Tanya A., McGowan, Sheena, Whisstock, James C., Pike, Robert N., Kemp, David J., Buckle, Ashley M., Monash), and Queensland Inst. of Med. Rsrch.). Fri . "Structural Mechanisms of Inactivation in Scabies Mite Serine Protease Paralogues". United States. doi:10.1016/j.jmb.2009.04.082.
@article{osti_1005763,
title = {Structural Mechanisms of Inactivation in Scabies Mite Serine Protease Paralogues},
author = {Fischer, Katja and Langendorf, Christopher G. and Irving, James A. and Reynolds, Simone and Willis, Charlene and Beckham, Simone and Law, Ruby H.P. and Yang, Sundy and Bashtannyk-Puhalovich, Tanya A. and McGowan, Sheena and Whisstock, James C. and Pike, Robert N. and Kemp, David J. and Buckle, Ashley M. and Monash) and Queensland Inst. of Med. Rsrch.)},
abstractNote = {The scabies mite (Sarcoptes scabiei) is a parasite responsible for major morbidity in disadvantaged communities and immuno-compromised patients worldwide. In addition to the physical discomfort caused by the disease, scabies infestations facilitate infection by Streptococcal species via skin lesions, resulting in a high prevalence of rheumatic fever/heart disease in affected communities. The scabies mite produces 33 proteins that are closely related to those in the dust mite group 3 allergen and belong to the S1-like protease family (chymotrypsin-like). However, all but one of these molecules contain mutations in the conserved active-site catalytic triad that are predicted to render them catalytically inactive. These molecules are thus termed scabies mite inactivated protease paralogues (SMIPPs). The precise function of SMIPPs is unclear; however, it has been suggested that these proteins might function by binding and protecting target substrates from cleavage by host immune proteases, thus preventing the host from mounting an effective immune challenge. In order to begin to understand the structural basis for SMIPP function, we solved the crystal structures of SMIPP-S-I1 and SMIPP-S-D1 at 1.85 {angstrom} and 2.0 {angstrom} resolution, respectively. Both structures adopt the characteristic serine protease fold, albeit with large structural variations over much of the molecule. In both structures, mutations in the catalytic triad together with occlusion of the S1 subsite by a conserved Tyr200 residue is predicted to block substrate ingress. Accordingly, we show that both proteases lack catalytic function. Attempts to restore function (via site-directed mutagenesis of catalytic residues as well as Tyr200) were unsuccessful. Taken together, these data suggest that SMIPPs have lost the ability to bind substrates in a classical 'canonical' fashion, and instead have evolved alternative functions in the lifecycle of the scabies mite.},
doi = {10.1016/j.jmb.2009.04.082},
journal = {J. Mol. Biol.},
number = (4) ; 07, 2009,
volume = 390,
place = {United States},
year = {Fri Aug 07 00:00:00 EDT 2009},
month = {Fri Aug 07 00:00:00 EDT 2009}
}