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Ides and Speb Studies on secreted cysteine proteases of Streptococcus pyogenes - IdeS and SpeB Reine Vindebro Department of Molecular Biology Umeå University Umeå 2014 Responsible publisher under swedish law: the Dean of the Medical Faculty This work is protected by the Swedish Copyright Legislation (Act 1960:729) ISBN: 978-91-7601-048-8 ISSN: 0346-6612 New series nr: 1646 Electronic version available at http://umu.diva-portal.org/ Printed by: KBC printing service (Umeå University) Umeå, Sweden 2014 To Sofia and Rasmus. i ii Table of Contents Abstract iv List of Publications and Manuscripts v Abbreviations vi 1 Introduction 1 1.1 Streptococcus pyogenes 1 1.1.1 Virulence factors 2 1.2 Proteases in general 3 1.3 Immunoglobulin G (IgG) 3 1.4 IdeS 5 1.4.1 Discovery 5 1.4.2 Protein properties and structure 6 1.4.3 Substrate specificity and binding site on IgG 7 1.4.4 Enzymatic constants 9 1.4.5 Effect of IgG cleavage 10 1.4.6 IdeS as a dimer 11 1.4.7 Allelic Variation 12 1.4.8 Other functions of IdeS 13 1.4.9 Prevalence of IdeS in S. pyogenes strains 14 1.4.10 Regulatory control 14 1.4.11 Importance as a virulence factor 15 1.4.12 Homologues in other bacterial species 16 1.4.13 Therapeutic potential 17 1.4.14 Use as a laboratory tool 17 1.5 SpeB 18 1.5.1 Discovery 18 1.5.2 Regulatory control 18 1.5.3 Structure of SpeB and the potential dimer 18 1.5.4 Functions of, and substrates for, SpeB 19 1.5.5 IgG as a substrate for SpeB 20 1.5.6 SpeB is, or is not, an important virulence factor 21 1.6 IdeS and SpeB as virulence factors 22 2 Methods 24 2.1 General methods 24 2.2 Detecting degradation of IgG by IdeS 25 3 Results and discussion 28 3.1 Paper I 28 3.2 Paper II 30 3.3 Paper III 31 3.4 Paper IV 33 3.5 Paper V 34 Conclusions 36 Acknowledgements 37 References 38 iii Abstract The pathogen Streptococcus pyogenes is a significant cause of human morbidity and mortality. Most of the work in this thesis is focused on streptococcal virulence factor IdeS, but the thesis also features work on SpeB, another streptococcal virulence factor. Both IdeS and SpeB are secreted cysteine proteases and both have previously been shown to degrade human IgG. IgG is the only known substrate for IdeS while SpeB is a more promiscuous protease with a larger number of identified substrates. A significant part of the data presented in this thesis is the result of designing and optimizing methods to detect and accurately measure the proteolytic degradation of IgG. Methods aimed at measuring the binding interactions between enzyme and substrate have also been frequently utilized. I show that IdeS is a monomeric protease, as opposed to previously published data that suggested it to be dimeric. IdeS cleaves the two heavy chains of IgG in a two-step reaction and I demonstrate that the first cleavage is magnitudes faster than the second one. This means that IdeS is a more efficient enzyme than previously thought. The difference in rate cannot completely be explained by a loss of affinity between IdeS and IgG after the cleavage of the first heavy chain. The velocity of IdeS is further increased by the presence of human Cystatin C, via an unknown mechanism. Cystatin C is normally a protease inhibitor and it having an opposite effect is puzzling. The synthesis and evaluation of novel inhibitors are also described. Peptide analogues mimicking the sequence surrounding the scissile bond on IgG - with an amino acid replaced with a more rigid motif - act as specific, but low-affinity, inhibitors of IdeS. The peptide analogues’ inhibitory capacity for SpeB and papain was also assayed. When it comes to SpeB, I show that it does not have IgG as a substrate under physiological conditions, in contrast to what was previously thought. This thesis does not only present findings on the IgG degrading capacity of IdeS and SpeB but also include data on fundamental enzymatic properties for these proteases. iv List of Publications and Manuscripts I. Vindebro R, Spoerry C, von Pawel-Rammingen U. Rapid IgG heavy chain cleavage by the streptococcal IgG endopeptidase IdeS is mediated by IdeS monomers and is not due to enzyme dimerization. FEBS Lett. 2013 Jun 19;587(12):1818-22 II. Berggren K, Vindebro R, Bergström C, Spoerry C, Persson H, Fex T, Kihlberg J, von Pawel-Rammingen U, Luthman K. 3-aminopiperidine-based peptide analogues as the first selective noncovalent inhibitors of the bacterial cysteine protease IdeS. J Med Chem. 2012 Mar 22;55(6):2549-60 III. Persson H, Vindebro R, von Pawel-Rammingen U. The streptococcal cysteine protease SpeB is not a natural immunoglobulin- cleaving enzyme. Infect Immun. 2013 Jun;81(6):2236-41 IV. Vincents B, Vindebro R, Abrahamson M, von Pawel-Rammingen U. The human protease inhibitor cystatin C is an activating cofactor for the streptococcal cysteine protease IdeS. Chem Biol. 2008 Sep 22;15(9):960-8 V. Vindebro R, von Pawel-Rammingen U. Insights into substrate recognition and biochemical properties of the streptococcal IgG endopeptidase IdeS Preliminary manuscript v Abbreviations IdeS - IgG-degrading enzyme of S. pyogenes SpeB - Streptococcal pyrogenic exotoxin B IgG - Immunoglobulin G scIgG - single cleaved IgG SEC - size exclusion chromatography SPR - surface plasmon resonance ITC - isothermal titration calorimetry SDS-PAGE - sodium dodecyl sulfate polyacrylamide gel electrophoresis. vi 1 Introduction This thesis describes various characteristics of two virulence factors secreted by the pathogenic bacteria Streptococcus pyogenes. These two proteins, IgG-degrading enzyme of S. pyogenes (IdeS) and Streptococcal pyrogenic exotoxin B (SpeB), are both proteases and capable of altering the course of an infection by degrading proteins of human or bacterial origin. The substrate for these proteases most central to this thesis is Immunoglobulin G (IgG). This introduction will give a short overview of the bacterium, including some of its other virulence factors; of the mechanism of proteases in general; and of the structure and function of IgG; before going into more depth on IdeS in particular, but also on SpeB. The thesis tries to answer questions related to molecular biology, such as the role of a virulence factor, by using tools often more related to biochemistry than molecular biology. This will be evident by the focus on both the molecular biological and biochemical aspects of the investigated proteins. The research at the intersection between molecular biology and biochemistry was necessary due to the requirement of a deeper understanding of some biochemical aspects to be able to advance on the molecular biology aspects of the proteins of interest. 1.1 Streptococcus pyogenes Streptococci have long been known to be a causative agent of various human diseases. This has led to a vast amount of research on the subject. Streptococci are Gram-positive non-motile cocci that are predominantly extracellular pathogens, but have also been described to occasionally reside inside cells. Streptococcus pyogenes is part of a group of hemolytic streptococcal strains. S. pyogenes can cause numerous pathological conditions and sequelae, with widely varying severity. S. pyogenes usually infects either the throat or the skin (1). Certain strains, identified by allelic variation of the M-protein surface antigen, are more prone to cause throat infections, while other strains are more prone to cause skin infections. Uncomplicated pathological conditions such as pharyngitis (strep throat), impetigo, and scarlet fever are most common. Invasive disease and some sequelae can be life threatening, but are fortunately much less prevalent. Severe conditions caused directly, or indirectly as sequelae, by S. pyogenes include erysipelas, cellulitis, rheumatic fever, rheumatic heart disease, post-streptococcal glomerulonephritis, necrotizing fasciitis (flesh-eating disease), and streptococcal toxic shock syndrome (STSS). S. pyogenes causes millions of cases of severe disease and hundreds of millions of non-severe infections, qualifying it for a spot in the top ten list of pathogens based on mortality (2). S. pyogenes infections thus are a significant cause of morbidity and mortality, evident primarily in low-income countries (2). S. pyogenes was differentiated from other hemolytic streptococcal species by Rebecca Lancefield in the late 1920s. Serological tests on “substance C” could differentiate between hemolytic streptococci of human origin, and streptococci collected from other species of animal (3,4). The streptococci from human origin were labeled “Group A”, and thus S. pyogenes is also known as Group A Streptococci (GAS) in current literature. The “substance C” are cell wall carbohydrates for most of the Lancefield groups, and the GAS-specific 1 carbohydrate has been identified as N-acetyl-β-D-glucosamine linked to a polymeric rhamnose backbone (5). S. pyogenes is further divided by the serological differentiation of the surface exposed M-protein, or more recently, the sequence of the corresponding emm-gene. Incidentally, Rebecca Lancefield was also highly involved in the classification of M-types (6). There are today over 200 unique M-types identified among pathogenic S. pyogenes isolates, the most common being M1, M3, M4, M12, M28, and M89, although large differences in frequency of specific M-types exist depending on the geographical region investigated (1,7,8). 1.1.1 Virulence factors S. pyogenes is a strictly human pathogen, although there are animal models for certain pathologies. The bacterium has evolved a substantial arsenal of virulence factors enabling it to survive and proliferate in the human host. Some factors are important for adhesion, nutrient acquisition, modulation of coagulation etc., but will not be discussed in this thesis. Many of the virulence factors have the capability of altering the immune system’s detection of and response to infection.
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