Structural basis of bacterial defense against g-type lysozyme-based innate immunity
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Cellular and Molecular Life Sciences
RESEARCH ARTICLE
Structural basis of bacterial defense against g-type lysozyme-based innate immunity S. Leysen • L. Vanderkelen • S. D. Weeks C. W. Michiels • S. V. Strelkov
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Received: 14 August 2012 / Revised: 21 September 2012 / Accepted: 27 September 2012 / Published online: 21 October 2012 Ó Springer Basel 2012
Abstract Gram-negative bacteria can produce specific proteinaceous inhibitors to defend themselves against the lytic action of host lysozymes. So far, four different lysozyme inhibitor families have been identified. Here, we report the crystal structure of the Escherichia coli periplasmic lysozyme inhibitor of g-type lysozyme (PliG-Ec) in complex with Atlantic salmon g-type lysozyme (SalG) at ˚ , which is exceptionally high for a a resolution of 0.95 A complex of two proteins. The structure reveals for the first time the mechanism of g-type lysozyme inhibition by the PliG family. The latter contains two specific conserved regions that are essential for its inhibitory activity. The inhibitory complex formation is based on a double ‘keylock’ mechanism. The first key-lock element is formed by the insertion of two conserved PliG regions into the active site of the lysozyme. The second element is defined by a distinct pocket of PliG accommodating a lysozyme loop. Computational analysis indicates that this pocket represents a suitable site for small molecule binding, which opens an avenue for the development of novel antibacterial agents that suppress the inhibitory activity of PliG. Keywords Lysozyme inhibitor PliG Lysozyme Innate immunity Inhibitory complex Crystal structure
S. Leysen S. D. Weeks S. V. Strelkov (&) Laboratory for Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, Herestraat 49 bus 822, 3000 Leuven, Belgium e-mail: [email protected] L. Vanderkelen C. W. Michiels Laboratory of Food Microbiology, Leuven Food Science and Nutrition Research Centre (LFoRCe), Katholieke Universiteit Leuven, Kasteelpark Arenberg 22, 3001 Leuven, Belgium
Introduction Lysozyme (EC 3.2.1.17) is an important enzyme of the innate immune system. It makes bacteria sensitive to osmotic lysis by degrading peptidoglycan, a vital component of the cell wall. Specifically, lysozyme catalyzes the hydrolysis of the b1-4 glycosidic bond between N-acetyl muramic acid (NAM) and N-acetyl glucosamine (NAG), which constitute the disaccharide building blocks of peptidoglycan polymers. Based on amino acid sequence similarity, lysozymes in the animal kingdom were classified as c-(conventional or chicken), g-(goose) or i-(invertebrate) type [1]. In their substrate binding cleft, there are six consecutive subsites for binding NAG and/or NAM molecules. These subsites are labelled A–F for c-type and i-type lysozymes, and B–G for g-type lysozymes. In all cases, the bond cleavage occurs between the NAM and NAG molecules occupying subsites D and E [2–4]. C-type and i-type lysozymes cleave the glycosidic bond with
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