Structural mechanisms of inactivation in scabies mite serine protease paralogues

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