Talk:SB2013 L08gr1
From Proteopedia
The Imporance of OspC in Lyme Disease
Lyme disease is a progressive multisystem disorder that produces a primary infection (erythema migrans), at an early stage, at the site of bite by Ixodes tick carrying spirochetes (Borrelia burgdorferi) and may spread to secondary sites (e.g. heat, nervous system, joints), if left untreated. Outer Surface Proteins (e.g. OspA, OspB and OspC) play a vital role in this infecting process. While inside the vector, presence of OspA is prominent while OspC is unexpressed on the spirochete outer membrane. When spirochetes invade the host body, OspA is suppressed and an upregulation of OspC occurs due to an induction in OspC synthesis (the surface proteins are co-regulated on the mRNA level). This upregulation of OspC occurs partially due to differential temperature change (the optimal temperature being 32-37 degrees C) in the host body. However, OspC expression decreases after 2 days (time needed for spirochete transmission) of feeding. This implies that OspC is a vital protein supporting the primary transmission of the antigen in the host body (Kumaran et al. 2001). Furthermore, the tick-borne infection was shown to be prevented upon addressing active (Gilmore et. al 1996) or passive (Mbow et. al 1999) immunization with various OspC formulations in experimental mammals. As a result, OspC is the protein of interest that is to be studied.
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OspC Structure
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| 1ggq, resolution 2.51Å () | |||||||||
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| Related: | 1f1m, 1osp, 1fj1 | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
The highly variable OspC gene is located on a 27 kb circular plasmid and encodes for lipoprotein, which contains an 18 amino acid sequence. This amino acid sequence changes after processing and lipidation at the amino proximal Cys residue. The high variability of OspC gene makes OspC protein very polymorphic which varies among the major groups and even within different locations (Kumaran et al. 2001). It is also important to note that there is a high variance in the amino acid sequence of the invasive from non-invasive species, contributing to the differentiation of folding and solvent structures of putative sites. The three dimensional of OspC consists of five helices and two anti-parallel beta sheets per monomer (Figure 1). Not all strains of OspC are invasive to humans (less than half). Even within invasive groups, the amino acid sequence varies (dissimilarity in building units), yet all of the invasive groups continue to share remarkably well reserved solvent structures (Figure 5) within the cavity (similarity in 3D structure and folding leading to a similar function). Another point of significance to be added is that regions in all invasive species are likely to be partially occupied by heavy trace ions (Kumaran et al. 2001).One of the most prominent differences between OspC of invasive species and that of a non-invasive species is that OspC found on invasive strands of spirochetes has a strong negative electrostatic potential region which exists within its two-fold axis (Figure 2).
Structural Function
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The importance of this negative region is immense because it is likely to have a variety of functions. Initially it has been proposed that OspC may function in the cellular adhesion of Lyme disease because of its predisposition to bind to positively charged host ligands, such as extracellular glycoproteins like fibronectin. But more recent studies have suggested that the function of OspC may be entirely different. It is now understood that OspC plays a role in immobilizing plasminogen, suggesting that OspC is a biologically relevant plasminogen receptor on the surface of B. burgdorferi. Lyme disease, like many bacterial pathogens, cannot produce endogenous membrane-associated proteases and has to appropriate host proteases to increase the probability of successful host colonization (Önder et al. 2011).
Immune Response
However, the existence of the negatively charged region may not be the only reason contributing the invasion. Overall structure of OspC may play an equally important role. Recent studies showed that, in serum of patients demonstrating erythema migrans (early stage of Lyme disease), IgM antibody has been found to interact with OspC (Wilske et. al 1986). On the other hand, immunoblot of serum from patients showing secondary infection has been observed to demonstrate a lower number of IgM-OspC complexes, further demonstrating the importance of OspC for the primary transmission (Dressler et. al 1993). In addition, moderate IgG reactivity to OspC has been found in the serum of patients at an early stage of Lyme disease (Fung et al 1994). Furthermore, supporting researches have highlighted a well-conserved immunodominant epitope located on the region of OspC demonstrating the ability of binding to antibodies (Jobe et. al 2003). IgM and IgG antibodies from serum of patients at an early stage of Lyme disease get absorbed with a carboxy-terminal (seven amino acid long) of OspC.(Figure 6) Surprisingly, this epitope on the carboxy-terminal and its binding of antibodies is very well conserved among different invasive OspC proteins (Lovrich et. al 2005).
Super Vaccination
Since OspC helps with early transmission of spirochete to the host body, it will be much more efficient to develop a vaccine based on OspC compared to the current vaccination based on OspA (Kumaran et al. 2001). In addition, a combinatory vaccination based on both OspA and OspC may be developed to not only produce antibody in the host body responding to OspC but also disinfecting the tick while it feeds on the host blood containing antibodies for OspA (Greenberg 2001). Nevertheless, due to high variance in structure (within invasive groups, which can even vary depending on location), it is a matter of difficulty to produce a globalized vaccination (Kumaran et al. 2001). A globalized vaccination may work by denaturing the structure of OspC and making it impossible for it to bind is to host cells. A proposed target area for a vaccine may include areas like the well-conserved immunodominant epitope present at the carboxy-terminal of OspC (Jobe et. al 2003).
