G18secL03Tpc4
Outer surface protein C (OspC) of Borrelia burgdorferi is one of the major antigens on the surface of the Lyme disease spirochete, Borrelia burgdorferi, along with other outer surface proteins A and B (OspA and OspB, respectively). It greatly differs from OspA and OspB in both structure and function. The uniqueness of OspC is that it comes into play when the pathogen is being transmitted to humans or other mammals.OspC is critical for survival in or transmission to the tick or mammalian host.[1] OspC is being produced by Borrelia burgdorferi during a very short time interval when infected ticks start feeding, but its synthesis is known to slow down greatly after transmission to a mammalian host. Interestingly, when an infested tick engorges, B. burgdorferi within the gut multiply and downregulate ospA. At the same time, the spirochetes start producing OspC in the feeding gut and continue to produce OspC throughout the transmission process and during the establishment of early vertebrate infection. This pattern of expression suggests that OspC may serve a function in the tick, possibly facilitating the migration of the spirochete from the vector gut to the salivary glands during transmission. After transmission from the tick, OspC may also play a role in colonization of host tissues.[2] It was demonstrated that those spirochetes that lack OspC are capable to replicate inside and migrate to the salivary glands of the tick vector but do not infect mammals. [3] Without OspC the spirochetes are believed to be unable to adapt to the environment inside the host. Therefore, OspC is believed to determine virulence of the spirochete to mammals, including humans. ContentsBasic Structure DescriptionOspC proteins are highly polymorphic and this variability extends even to strains collected from a single geographical area. [3] The outer surface protein C (ospC) locus Borrelia burgdorferi is at least an order of magnitude more variable than other genes in the species.[4]
The ospC gene is located on a 27 kb circular plasmid and encodes a lipoprotein of 22–23 kDa.[5] The protein is initially synthesized with an 18-amino-acid-long signal sequence which is removed during processing and lipidation at the amino proximal Cys residue. Each unit contains 162 amino acid residues.
OspC is predominantly α-helical in its secondary structure. β-sheets are also present, but they are rather short and not promininent. The molecule also contains six random coils throughout the structure on each subunit. OspC is unique when compared to its sister proteins, OspA and OspB, which are made up of beta-sheets mostly.[4]
A single OspC monomer subunit is composed of 4 long and 1 short α-helices. Also, 2 short segments of β-sheets are observed near the binding site of the molecule.
OspC is a dimerized molecule, with 2 identical monomeric subunits comprising a dimer. However, for a binding event to occur, a tetramer made up of two dimers is necessary. Major Hypothesized Functions
Borrelia burgdorferi expresses OspA but not OspC when residing in the midgut of unfed ticks. However, when the tick starts feeding on mammals, OspC synthesis is induced and OspA is repressed.The switch is in part due to the change in temperature; OspC is induced at 32–37°C, but not at 24°C, and this upregulation is at the transcriptional and translational levels. Evidence suggests co-regulation of these two genes at the mRNA level. Clearly, to survive in both hosts, spirochetes have evolved mechanisms for sensing the different host environments and responding accordingly.[3]
OspC may possibly be a binding protein contributing to a fundamental biological process and determining virulence of the bacteria. Several studies have shown that B.burgdorferi has a predilection for collagenous tissue and can interact with fibronectin and cellular collagens. The spirochetes can bind to a number of different cell types, including fibroblasts. Borrelia burgdorferi can bind to a novel circulating fibroblast-like cell called the peripheral blood fibrocyte, which expresses collagen types I and III as well as fibronectin, in a process that does not require OspA or OspB.[6] Putative Binding SiteThe binding site of OspC is believed to be located on the surface that projects away from the membrane and has a region with strong negative electrostatic potential. Cavities are formed at the top of the molecule away from the membrane surface. Each cavity has a volume of 50 Å3 and is formed by residues Ala75, Ile76, Gly77, Lys78, Lys79, Glu89, Ala90, Asp91, His92 and Asn93 of one monomer, and Gly94, Ser95, Ser98, Gly146, Lys147 and Glu148 of the other monomer.[3] Positively charged Magnesium ion Mg2+ between the two dimers demonstrates the location of hypothesized binding site. Fibronectin in humans, according to the study of its crystal structure, is positively charged, indicating a ligand to which the bacteria can bind through the use of OspC.[7] Role of OspC in Lyme DiseaseNot every strain of B. burgoderferi causes Lyme disease in humans, and the type of OspC expressed indicates whether the bacteria is harmful or not. The disease causing bacteria, the invasive strains, contain OspC which has the highly negative section, like that of the B31 type, while the non-harmful strains, or non-invasive strains, lack this negative charge in that region of the protein. The negatively charged region may be involved in binding to positively charged host ligands. [3] This suggests that the OspC protein is responsible for the pathogenicityof B. burgoderferi, and thus responsible for causing Lyme disease. OspC-based Vaccine Against Lyme DiseaseResearchers believe that an OspC based vaccine would be more effective against Lyme disease than the current OspA based vaccine once further research is conducted regarding the three dimensional structure of OspC's, especially the structure of invasive strains. [3] An OspC vaccine would have significant advantages over the current OspA vaccine, but there are several problems that require further research before the vaccine can be made. Main Advantages of Developing OspC-based VaccineUnlike OspC, the OspA protein is only present in the Borrelia burgdorferi while they are in the midgut of the cold blooded tick, and not in the host. Once the tick begins to feed on its warm blooded mammalian host, the Borrelia burgdorferi migrate from the midgut of the tick to the salivary glands and OspC is produced in the host's bloodstream. [8] Because of this, when a host is vaccinated with the OspA vaccine, antibodiesto the OspA protein can only kill the bacteria inside of the tick if it ingests the antibodies during feeding. [8] If the bacteria enter the host, it can differentiate into several forms for which the vaccine cannot protect against. In contrast, an OspC based vaccine would allow the host to make antibodies to kill the Borrelia burgdorferi after they enter the host's body. [8] Main Problems with Application of OspC-based VaccineThe major problem with creating an OspC based vaccine is a lack of knowledge regarding the three dimensional structure of the different variants of the OspC protein, especially those from invasive strains. [8] The OspC locusof Borrelia burgdorferi is much more variable than other genes in the species. There are 22 OspC major groups, with 15 of those found in the northeastern United States.[4] In a study run by researchers at the University of California Davis, it was found that OspA genes from 3 isolates were greater than 99% homologous, while OspC genes shared only 81%-85% homology. [9] The genetic and antigenic heterogeneity associated with OspC, but not OspA, may limit the effectiveness of an OspC based vaccine, since the vaccine would not protect against all of the strains. [9] Necessity of Further Research on OspCThe biological function of OspC is not yet completely understood. Further investigation is required to determine OspC ecology and its relatedness to the pathogenicity of B. Burgdorferi. For the development of an effective OspC-based vaccine, it is important to know representative three-dimensional structures of at least a few more OspCs, especially those from the invasive strains. This information could be useful for rational design of an OspC-based recombinant vaccine.[3] Also, further understanding of the evolution and genetics of Lyme Disease cause, Borrelia burgdorferi, with its outer surface proteins such as OspC, fosters progress toward ecologically based control efforts.[10]
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3D Structures
Notes and References
Proteopedia Page Contributors and Editors (what is this?)
Ekaterina Shnaydman, Olivia Cary, Paramjit Singh, Michal Harel, Alexander Berchansky
