G18secL03Tpc4: Difference between revisions
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< | <StructureSection load='' size='450' side='right' scene='G18secL03Tpc4/Top3dimage/1' caption=''> | ||
'''Outer surface protein C (OspC) of ''Borrelia burgdorferi''''' | '''Outer surface protein C (OspC) of ''Borrelia burgdorferi''''' | ||
is one of the major [http://en.wikipedia.org/wiki/Antigen antigens] on the surface of the [http://en.wikipedia.org/wiki/Lyme_disease Lyme disease] [http://en.wikipedia.org/wiki/Spirochaete spirochete], [http://en.wikipedia.org/wiki/Borrelia_burgdorferi ''Borrelia burgdorferi''], along with other outer surface proteins A and B ([http://www.proteopedia.org/wiki/index.php/OspA OspA] and [http://www.proteopedia.org/wiki/index.php/User:Marvin_O%27Neal/Antibody_OspA_and_OspB 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.<ref>PMID:11169111</ref> 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.<ref>PMID:14722614</ref> 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. <ref name="Kum">D. Kumaran1, S. Eswaramoorthy1, B.J. Luft2, S. Koide3, J.J. Dunn1, C.L. Lawson1,4 and S. Swaminathan1. Crystal structure of outer surface protein C (OspC) from the Lyme disease spirochete, Borrelia burgdorferi.The EMBO Journal (2001) 20, 971 - 978 [http://dx.doi.org/DOI:10.1093/emboj/20.5.971]</ref> Without OspC the spirochetes are believed to be unable to adapt to the environment inside the host. Therefore, OspC is believed to determine [http://en.wikipedia.org/wiki/Virulence virulence] of the spirochete to mammals, including humans. | is one of the major [http://en.wikipedia.org/wiki/Antigen antigens] on the surface of the [http://en.wikipedia.org/wiki/Lyme_disease Lyme disease] [http://en.wikipedia.org/wiki/Spirochaete spirochete], [http://en.wikipedia.org/wiki/Borrelia_burgdorferi ''Borrelia burgdorferi''], along with other outer surface proteins A and B ([http://www.proteopedia.org/wiki/index.php/OspA OspA] and [http://www.proteopedia.org/wiki/index.php/User:Marvin_O%27Neal/Antibody_OspA_and_OspB 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.<ref>PMID:11169111</ref> 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.<ref>PMID:14722614</ref> 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. <ref name="Kum">D. Kumaran1, S. Eswaramoorthy1, B.J. Luft2, S. Koide3, J.J. Dunn1, C.L. Lawson1,4 and S. Swaminathan1. Crystal structure of outer surface protein C (OspC) from the Lyme disease spirochete, Borrelia burgdorferi.The EMBO Journal (2001) 20, 971 - 978 [http://dx.doi.org/DOI:10.1093/emboj/20.5.971]</ref> Without OspC the spirochetes are believed to be unable to adapt to the environment inside the host. Therefore, OspC is believed to determine [http://en.wikipedia.org/wiki/Virulence virulence] of the spirochete to mammals, including humans. | ||
=== Basic Structure Description === | === Basic Structure Description === | ||
OspC proteins are highly [http://en.wikipedia.org/wiki/Polymorphism_(biology) polymorphic] and this variability extends even to strains collected from a single geographical area. <ref name="Kum" | OspC proteins are highly [http://en.wikipedia.org/wiki/Polymorphism_(biology) polymorphic] and this variability extends even to strains collected from a single geographical area. <ref name="Kum"/> The outer surface protein C (ospC) locus ''Borrelia burgdorferi'' is at least an order of magnitude more variable than other genes in the species.<ref name="Brisson">PMID:15514047</ref> | ||
*Primary Structure | *Primary Structure | ||
The ospC gene is located on a 27 kb [http://en.wikipedia.org/wiki/Plasmid circular plasmid] and encodes a [http://en.wikipedia.org/wiki/Lipoprotein lipoprotein] of 22–23 kDa.<ref>PMID:7679385</ref> The protein is initially synthesized with an 18-amino-acid-long signal sequence which is removed during processing and [http://en.wiktionary.org/wiki/lipidated lipidation] at the amino proximal Cys residue. Each unit contains 162 amino acid residues. | The ospC gene is located on a 27 kb [http://en.wikipedia.org/wiki/Plasmid circular plasmid] and encodes a [http://en.wikipedia.org/wiki/Lipoprotein lipoprotein] of 22–23 kDa.<ref>PMID:7679385</ref> The protein is initially synthesized with an 18-amino-acid-long signal sequence which is removed during processing and [http://en.wiktionary.org/wiki/lipidated lipidation] at the amino proximal Cys residue. Each unit contains 162 amino acid residues. | ||
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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 [http://en.wikipedia.org/wiki/Collagen collagenous] tissue and can interact with [http://en.wikipedia.org/wiki/Fibronectin fibronectin] and cellular collagens. The spirochetes can bind to a number of different cell types, including [http://en.wikipedia.org/wiki/Fibroblast 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.<ref>PMID:10072447</ref> | 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 [http://en.wikipedia.org/wiki/Collagen collagenous] tissue and can interact with [http://en.wikipedia.org/wiki/Fibronectin fibronectin] and cellular collagens. The spirochetes can bind to a number of different cell types, including [http://en.wikipedia.org/wiki/Fibroblast 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.<ref>PMID:10072447</ref> | ||
==== Putative Binding Site ==== | ==== Putative Binding Site ==== | ||
The <scene name='G18secL03Tpc4/Binding_site/1'>binding site</scene> 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. <scene name='G18secL03Tpc4/Binding_site_single_dimer/1'>Cavities</scene> 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.<ref name="Kum"/> Positively charged Magnesium ion | The <scene name='G18secL03Tpc4/Binding_site/1'>binding site</scene> 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. <scene name='G18secL03Tpc4/Binding_site_single_dimer/1'>Cavities</scene> 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.<ref name="Kum"/> Positively charged Magnesium ion | ||
<scene name='G18secL03Tpc4/Mg_ion/1'>Mg2+</scene> between the two dimers demonstrates the location of hypothesized binding site. | <scene name='G18secL03Tpc4/Mg_ion/1'>Mg2+</scene> between the two dimers demonstrates the location of hypothesized binding site. | ||
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=== Role of OspC in Lyme Disease === | === Role of OspC in Lyme Disease === | ||
Not 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, | Not 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 [http://en.wikipedia.org/wiki/Ligand ligands]. <ref name="Kum"/> This suggests that the OspC protein is responsible for the [http://en.wikipedia.org/wiki/Pathogenicity pathogenicity]of B. burgoderferi, and thus responsible for causing Lyme disease. | ||
=== OspC-based Vaccine Against Lyme Disease === | === OspC-based Vaccine Against Lyme Disease === | ||
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==== Main Advantages of Developing OspC-based Vaccine ==== | ==== Main Advantages of Developing OspC-based Vaccine ==== | ||
Unlike 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. <ref name="Green">D. Greenburg, M.S. Rowe. Brookhaven Scientists Determine Key Lime Disease Protein Structure.Brookhaven National Laboratory (2001)[http://www.bnl.gov/bnlweb/pubaf/pr/2001/bnlpr022801.htm]</ref> Because of this, when a host is vaccinated with the OspA vaccine, antibodies to the OspA protein can only kill the bacteria inside of the tick if it ingests the antibodies during feeding. <ref name="Green"/> 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. <ref name="Green"/> | Unlike 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. <ref name="Green">D. Greenburg, M.S. Rowe. Brookhaven Scientists Determine Key Lime Disease Protein Structure.Brookhaven National Laboratory (2001)[http://www.bnl.gov/bnlweb/pubaf/pr/2001/bnlpr022801.htm]</ref> Because of this, when a host is vaccinated with the OspA vaccine, [http://en.wikipedia.org/wiki/Antibody antibodies]to the OspA protein can only kill the bacteria inside of the tick if it ingests the antibodies during feeding. <ref name="Green"/> 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. <ref name="Green"/> | ||
==== Main Problems with Application of OspC-based Vaccine ==== | ==== Main Problems with Application of OspC-based Vaccine ==== | ||
The 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. <ref name="Green"/> The OspC locus of 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. <ref | The 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. <ref name="Green"/> The OspC [http://en.wikipedia.org/wiki/Locus_(genetics) locus]of 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.<ref name="Brisson"/> In a study run by researchers at the University of California Davis, it was found that OspA genes from 3 [http://en.wikipedia.org/wiki/Genetic_isolate isolates] were greater than 99% homologous, while OspC genes shared only 81%-85% [http://en.wikipedia.org/wiki/Homology_(biology) homology]. <ref name="Cadiz">R.B. Cadiz, M. Crawford, R.B. LeFebvre, W.S Probert. Immunization with Outer Surface Protein (Osp) A, but Not OspC, Provides Cross-Protection of Mice Challenged with North American Isolates of ''Borrelia'' ''Burgdorferi''. The Journal of Infectious Diseases 1997; Volume 175: 400-405. [http://www.jstor.org/discover/10.2307/30131660?uid=3739832&uid=2&uid=4&uid=3739256&sid=21101134072011]</ref> The genetic and antigenic [http://en.wikipedia.org/wiki/Genetic_heterogeneity 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. <ref name="Cadiz"/> | ||
=== Necessity of Further Research on OspC === | === Necessity of Further Research on OspC === | ||
The 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.<ref name="Kum"/> 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.<ref>PMID:20877579</ref> | The 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.<ref name="Kum"/> 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.<ref>PMID:20877579</ref> | ||
</StructureSection> | |||
=== 3D Structures === | === 3D Structures === | ||
[http://www.proteopedia.org/wiki/index.php/OspA OspA] | [http://www.proteopedia.org/wiki/index.php/OspA OspA] | ||
[http://www.proteopedia.org/wiki/index.php/OspB OspB] | |||
[http://www.proteopedia.org/wiki/index.php/1ggq OspC] | [http://www.proteopedia.org/wiki/index.php/1ggq OspC] | ||
[http://www.proteopedia.org/wiki/index.php/1f1m Cristal Structure of OspC] | |||
[http://www.proteopedia.org/wiki/index.php/Image:OspC_electro_potentials.jpg OspC Electro Potentials] | |||
[http://www.proteopedia.org/wiki/index.php/Image:1ggq.png OspC Strain B31] | |||
[http://www.proteopedia.org/wiki/index.php/1g5z OspC Strain N40] | |||
[http://www.proteopedia.org/wiki/index.php/1f1m OspC Mutant] | |||
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'''Notes and References'''<references/> | '''Notes and References'''<references/> | ||