Lipoproteins Of Streptococcus Pyogenes Role In Virulence Biology Essay

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Streptococcus pyogenes bacterium a worldwide known human pathogen is also known as the Group A Streptococcus, GAS. It is Gram-positive, non-motile, and spherical in shape which grows in long chains or pairs (Figure 1A). S.pyogenes is distinguished from the other streptococci by the presence of the Lance field Group A carbohydrate found on its cell wall and it produces large zone of beta-hemolysis ( haemoglobin released when the erythrocytes are completely disrupted) when grown on a plate enriched in blood agar (Figure 1B). Therefore it is known as the Group A (beta-haemolytic) Streptococcus (GAS).

Figure 1A Figure 1B

Figure 1A. S.pyogenes spherical in shape grown in long chains or pairs . Figure 1B. S.pyogenes produces large zone of beta-hemolysis on a blood agar plate.

Streptococcus pyogenes is a highly significant human pathogen due the fact that

humans are its natural host and sole reservoir. It can survive and multiply in

different anatomic sites in humans such as skin, throat, female urogenital tract, lower

gastrointestinal tract, and blood(Cunningham 2000).

GAS precisely and selectively interacts with host immune system, such as the immunoglobulin (Ig) and complements factors, also have remarkable adaptation and antiphagocytic capabilities.

Group A Streptococcal Infections is mainly caused by S.pyogenes resulting in severity and it is documented throughout the world in all sexes, races and age group. Diseases caused by GAS can be mild such as pharyngitis or impetigo but in extreme cases, it can lead to invasive diseases- cellulitis, bacteremia, necrotizing facilities and toxic shock syndrome (TSS).These disease are associated with high mortality and morbidity rates(Lei, Liu et al. 2004).

Bacterial Lipoproteins

The bacterial cell envelope is deemed to be great importance as it is the vital point for interaction between the bacterium and its environment. Bacterial cell envelope proteins carry out variety of important functions such as adhesion, nutrient acquisition and numerous amount of interaction with the host defences (Sutcliffe and Harrington 2002).

Gram-positive bacteria lack a retentive outer membrane and thus, they have evolved several mechanisms for anchoring proteins within their membrane. Of the several mechanisms that Gram-positive bacteria have evolved, N-terminal lipidation, a major mechanism which allows proteins to be anchored in the bacteria membrane and these proteins are known as bacterial lipoproteins (Lpps). These bacterial lipoproteins have their N-terminal modified with N-Acyl Diacyl Glyceryl group (Sutcliffe and Harrington 2002).

Lipid modification of bacterial proteins enables them to efficiently carry out their important functions between the cell wall and the environment (Braun et al, 1993). Lpps performs wide range of critical functions such as substrate binding proteins (SBPs) in ABC transporter system; in antibiotic resistance; in cell signalling; in protein export and folding; in sporulation and germination; in conjugation and various other functions (Sutcliffe and Russell 1995).

Thus, the functions of lipoproteins of Gram-positive bacteria are comparable to the surface proteins of Gram- negative bacteria. For example, the substrate binding proteins of the ABC transporter system are typically Lpp in Gram-positive bacteria as well as in Gram-negative bacteria(Sutcliffe and Russell 1995).

Structure of signal peptides from bacterial lipoproteins

Proteins to be exported across the cell membrane via the two distinct export pathways require proteins with N-terminal signal peptides for recognition. There are two types of signal peptides namely, Type I and Type II signal peptides.

Figure 2: Type I and Type II signal peptides via Sec and Tat Dependent Transport (a) General Secretory Pathway, (b) Tat System

Type I and Type II signal peptides composed of three distinct segments, a positively charged amino-terminal N, a central, H-(hydrophobic) region and a more polar carboxy terminal C- (cleavage region) (von Heijne 1989).

Within type I signal peptide, it sustains a recognition motif (A-X-A, where X can be any amino acid) for type I signal peptidase cleavage activity. In the case of Type II signal peptide, it contains the recognition motif sequence of (L-3-[A/S/T]-2-[G/A]--1-C+1) for type II signal peptidase and its cleavage site often referred as lipoprotein ‘lipobox’.

In comparison between the two export pathways recognising the signal peptides, the Tat system signal peptide has a conserved SRRXFLK sequence between N-region and H-region, within which the twin arginine (RR) motif which is almost absolutely conserved compared to that of Sec pathway signal peptide (Figure 2).

Translocation across cellular membrane

In order to reach their site of function, a significant proportion of newly synthesised proteins need to be translocated to outside of cell. This is done mainly via the general secretory (Sec) pathway and Tat (twin arginine protein transport) system. The difference between the two systems lies in whether the conformation of the translocated protein is folded or unfolded.

The Sec pathway is the predominant route of transportation of proteins across the cytoplasmic membrane among the two distinct pathways(Driessen and Nouwen 2008). In the Sec pathway, proteins with an unfolded conformation have to synthesised with N-terminal signal peptides which will be excised at a later stage during the exportation, via a signal peptidase situated on the cytoplasmic membrane. There have been findings in which some of the putative lipoproteins are exported via SecA2 dependent accessory pathway across the cytoplasmic membrane in unfolded state found in some of the Gram-positive bacteria but not all (Lenz, Mohammadi et al. 2003; Gibbons, Wolschendorf et al. 2007).

In Tat system, proteins with folded conformation, even oligomeric proteins are transported to cytoplasmic membrane (Sargent, Berks et al. 2006). Proteins bearing N â€"terminal signal peptide containing invariant and essential twin arginine motif, are targeted to Tat system for exportation. Lipoproteins precursors exported through Tat system are in a fully folded conformation were confirmed during an analysis of dimethyl sulphoxide (Dms) reductase in Gram-negative bacteria (Gralnick, Vali et al. 2006).

This indicates that Tat system is a mechanism which is fundamentally different from the Sec pathway and requires the proteins to be folded before they cross the cellular membrane.

Both translocation pathways require proteins bearing N-terminal signal peptides which are required for the recognition to be exported across the membrane. Proteins destined for lipidation contains a motif in their signal peptides also known as the lipobox which forwards them to lipoprotein biogenesis machinery after exportation via either Sec pathway or Tat system.

Lipoprotein Biogenesis

To attain their full fledged function, the newly synthesised pro-lipoproteins exported across the cytoplasmic membrane via the Sec pathway or Tat system will be channelled to the lipoprotein biogenesis machinery. This channelling process will be guided by the conserved motif (lipobox) in the protein signal peptide.

Figure 3: Biogenesis of Lipoproteins

Once the protein is exported across the cellular membrane with the guidance of the signal peptide II via Sec or Tat dependent system, the conserved cysteine residue within the lipobox of the signal peptide is modified with a diacyglycerol group attached through a thioether linkage. The above whole reaction is catalyzed by the enzyme prolipoprotein diacylglycerol transferase (Lgt), using phospholipid substrates (Qi, Sankaran et al. 1995; Sankaran, Gupta et al. 1995)

Once after the conserved residue gets lipdated, the signal peptide is cleaved within the lipobox by a specific lipoprotein signal peptidase II (Lsp), enzyme to release the lipidated cysteine as the N-terminal for the mature bacterial lipoprotein(Sankaran and Wu 1995) . Above mentioned steps for lipidation of Gram-positive bacteria, it was confirmed to be vital and sufficient.

In a third step modification of the lipoprotein in the biogenesis pathway would be the lipid modification of the lipoprotein by a fatty acylation of the amino group of the N-terminal diacylglycerol modified Cys to form N-acyl diacylglycerol Cysteine by the enzyme, lipoprotein amino acyl transferase. This enzyme is not conserved as its homologues are not available in the genomes of low G-C Gram positive bacteria (Tjalsma, Kontinen et al. 1999).

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