Structural mechanisms of inactivation in scabies mite serine protease paralogues

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. and Buckle, Ashley M. (2009) Structural mechanisms of inactivation in scabies mite serine protease paralogues. Journal of Molecular Biology, 390 4: 635-645. doi:10.1016/j.jmb.2009.04.082

Author 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.
Title Structural mechanisms of inactivation in scabies mite serine protease paralogues
Journal name Journal of Molecular Biology   Check publisher's open access policy
ISSN 0022-2836
Publication date 2009-07-24
Sub-type Article (original research)
DOI 10.1016/j.jmb.2009.04.082
Volume 390
Issue 4
Start page 635
End page 645
Total pages 11
Place of publication London, United Kingdom
Publisher Academic Press
Language eng
Formatted 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 Å and 2.0 Å 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.
Keyword Inactivated catalytic triad
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Veterinary Science Publications
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