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User:Bleonard4/Toxic Shock Syndrome Toxin

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Project Proposal

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Introduction

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A brief introduction expanding on the one already present in the article

Characteristics

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Toxic Shock Syndrome Toxin (TSST-1), a prototype superantigen secreted by a Staphylococcus aureus bacterium strain in susceptible hosts, acts on the vascular system by causing inflammation, fever, and shock [1]. TSST-1 is a bacterial exotoxin found in patients who have a menstruating or non-menstruating association with Toxic Shock Syndrome (TSS)[2]. TSST-1 can be found in men, women, children, and even non-menstruating women. Staphylococcus aureus bacteria that produces the TSST-1's in any area of the body, live mostly in the vagina of infected women. One-third of all Toxic Shock Syndrome (TSS) cases however, are found in men. This statistic could possibly be due to surgical wounds or any skin wound [3]. TSST-1 is the cause of 50% of non-menstrual and 100% of all menstrual TSS cases [4].

Structure

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TSST-1 has a molecular mass of 22 kilodaltons (kDa)[2]. In the nucleotide sequence of TSST-1, there is a 708 base-pair open-reading frame with a start codon of ATG, a Shine-Delgarno sequence which is seven base pairs downstream from the start site, and a stop codon of UAA that is further downstream[5]. In the entire nucleotide sequence, only 40 amino acids make up the signal peptide. A single signal peptide consists of a 1 to 3 basic amino acid terminus, a hydrophobic region of 15 residues, a Proline (Pro) or Gylcine (Gly) in the hydrophobic core region, a Serine (Ser) or Threonine (Thr) amino acid near the carboxyl terminal end of the hydrophobic core, and an Alanine (Ala) or Glycine (Gly) at the cleavage site[5]. A mature TSST-1 protein has a coding sequence of 585 base pairs[5]. The entire nucleotide sequence was determined by Blomster-Hautamaazg, et. al, as well as by other researchers with other experiments[5]. Consisting of a single polypeptide chain, the structure of holotoxin TSST-1 is three-dimensional and consists of an alpha (α) and beta (β) domain[6]. This three-dimensional structure of the TSST-1 protein was determined by purifying the crystals of the protein[6]. The two domains are adjacent from each other and possess unique qualities. Domain A, the larger of the two domains,contains residues 1-17 and 90-194 in TSST-1 and consists of a long alpha (α) helix with residues 125-140 surrounded by a 5-strand beta (β) sheet [6][4]. Domain B is unique because it contains residues 18-89 in TSST-1 and consists of a (β) barrel made up of 5 β-strands [6]. Crystallography methods show that the internal β-barrel of Domain B contains several hydrophobic amino acids and hydrophilic residues on the surface of the Domain, which allows TSST-1 to the cross mucous surfaces of epithelial cells [6]. Even though TSST-1 consists of several hydrophobic amino acids, this protein is highly soluble in water [4]. TSST-1 is resistant to heat and proteolysis. It has been proven that TSST-1 can be boiled more than an hour and still not have any damage done to its function[4].

Production

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TSST-1 is a protein encoded by the tstH gene, which is part of a mobile genetic element in the bacterial genome. [6] TSST-1 differs from other superantigens in that its genetic sequence does not have a homolog with other superantigen sequences. [6] When the protein is translated, it is in a pro-protein form, and can only leave the cell once a signal sequence has been cleaved off. [6] It also appears that the superantigenic and lethal portions of the protein are separate, based on studies of various mutations of the protein. [6]

Purification

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Samples of TSST-1 can be purified from bacterial cultures to use in in vitro testing environments, however this is not ideal due to the large number of factors that contribute to pathenogenesis in an in vivo environment. [7] Additionally, culturing bacteria in vitro provides an environment which is rich in nutrients, in contrast to the reality of an in vivo environment, in which nutrients tend to be more scarce. [7]

Mechanism

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The SAGs show remarkably conserved architecture and are divided into the N- and C- terminal domains. TSST-1 binds primarily to the alpha-chain of class II MHC exclusively through a low-affinity (or generic) binding site on the SAG N-terminal domain. This is opposed to other super antigens (SAGs) such as DEA and SEE, that bind to class II MHC through the low-affinity site, and to the beta-chain through a high-affinity site. This high-affinity site is a zinc-dependent site on the SAG C-terminal domain. When this site is bound, it extends over part of the binding groove, makes contacts with the bound peptide,and then binds regions of both the alpha and beta chains. MHC-binding by TSST-1 is partially peptide-dependent. Mutagenesis studies with SEA have indicated that both binding sites are required for optimal T-cell activation. These studies containing TSST-1 indicate that the TCR binding domain lies at the top of the back side of this toxin, though the complete interaction remains to be determined. A novel domain may exist in the SAGs that is separate from the TCR and class II MHC-binding domains. The domain consists of residues 150 to 161 in SEB, and similar regions exist in all the other SAGs as well. In this study a synthetic peptide containing this sequence was able to prevent SAG-induced lethality in D-galactosamine-sensitized mice with staphylcoccal TSST-1, as well as some other SAGs. [8]

References

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  1. ^ Todar, Kenneth. (2012). "Bacterial Protein Toxins". Todar's Online Textbook of Bacteriology. Madison, Wisconsin.
  2. ^ a b Edwin, Chitra, Parsonnet, Jeffrey, Kass, Edward H. (December 1988). "Structure-Activity Relationship of Toxic-Shock-Syndrome Toxin-1: Derivation and Characterization of Immunologically and Biologically Active Fragments". The Journal of Infectious Diseases 158(6): 1287.
  3. ^ Bushra, Joseph S. "Toxic Shock Syndrome Causes". eMedicineHealth.com. WebMD, Inc. Retrieved 3/28/12.
  4. ^ a b c d McCormick, John K., Tripp, Timothy J., et. al. (April 2012). "Functional Analysis of the TCR Binding Domain of Toxic Shock Syndrome Toxin-1 Predicts Further Diversity in MHC Class II/Superantigen/TCR Ternary Complexes". The Journal of Immunology 171:185-1392.
  5. ^ a b c d BLomster-Hautamaa, Debra A., Kreiswirth, Barry N,. et. al. (1986). "The Nucleotide and Partial Amino Acid Sequence of Toxic Shock Syndrome Toxin-1*." The Journal of Biological Chemistry 261 (33):15783-15786.a
  6. ^ a b c d e f g h i Dinges, M. M., P. M. Orwin, et al. (2000). "Exotoxins of Staphylococcus aureus." Clinical Microbiology Reviews 13(1): 16-34. Cite error: The named reference "Dinges" was defined multiple times with different content (see the help page).
  7. ^ a b Cunningham, R., A. Cockayne, et al. (1996). "Clinical and molecular aspects of the pathogenesis of Staphylococcus aureus bone and joint infections." Journal of Medical Microbiology 44(3): 157-164.
  8. ^ http://content.ebscohost.com/pdf17_20/pdf/2001/MIB/01Oct01/5367221.pdf?T=P&P=AN&K=5367221&S=R&D=eih&EbscoContent=dGJyMMvl7ESeprA4v%2BbwOLCmr0qep7VSsq24SLaWxWXS&ContentCustomer=dGJyMPGut1G3q7BKuePfgeyx44Dt6fIA

Division of Labor

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  • Hope will be responsible for expanding production and purification
  • Britney will be responsible for expanding characteristics
  • Emily will be responsible for expanding mechanism
  • All group members will contribute to formatting/reformatting as needed
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