G1SecL05: Difference between revisions
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=='''OspA + LA-2 Complex'''== | |||
==Background== | ==Background== | ||
[http://en.wikipedia.org/wiki/Lyme_disease Lyme disease], discovered in 1975<ref>PMID: 17160599</ref>, is a vector--borne disease caused by the inoculation of a [http://en.wikipedia.org/wiki/Spirochaete spirochaete], specifically ''[http://en.wikipedia.org/wiki/Borrelia_burgdorferi Borellia burgdorferi]'', into the skin by members of hard bodied ticks of the family ''[http://en.wikipedia.org/wiki/ Ixodes]''. Symptoms include arthritis at major joints, neurological problems such as reduced memory and poor ability to concentrate, and characteristic lesions ''erythema migans'', more commonly known as the bull’s eye rash. A major outer surface membrane protein of ''Borrelia'', ospA, plays a key role in immunity against Lyme disease through its binding to the LA-2 [http://en.wikipedia.org/wiki/Fragment_antigen-binding fab]. The Fragment Antigen Binding (fab) consists of a [http://en.wikipedia.org/wiki/Immunoglobulin_heavy_chain heavy chain] and [http://en.wikipedia.org/wiki/Immunoglobulin_light_chain light chain], with each respective region having its own constant and variable regions. | [http://en.wikipedia.org/wiki/Lyme_disease Lyme disease], discovered in 1975<ref>PMID: 17160599</ref>, is a vector--borne disease caused by the inoculation of a [http://en.wikipedia.org/wiki/Spirochaete spirochaete], specifically ''[http://en.wikipedia.org/wiki/Borrelia_burgdorferi Borellia burgdorferi]'', into the skin by members of hard bodied ticks of the family ''[http://en.wikipedia.org/wiki/ Ixodes]''. Symptoms include arthritis at major joints, neurological problems such as reduced memory and poor ability to concentrate, and characteristic lesions ''erythema migans'', more commonly known as the bull’s eye rash. A major outer surface membrane protein of ''Borrelia'', ospA, plays a key role in immunity against Lyme disease through its binding to the LA-2 [http://en.wikipedia.org/wiki/Fragment_antigen-binding fab]. The Fragment Antigen Binding (fab) consists of a [http://en.wikipedia.org/wiki/Immunoglobulin_heavy_chain heavy chain] and [http://en.wikipedia.org/wiki/Immunoglobulin_light_chain light chain], with each respective region having its own constant and variable regions. | ||
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===Structure of LA-2 OspA complex === | ===Structure of LA-2 OspA complex === | ||
<Structure load='1FJ1' size='400' frame='true' align='center' scene='Studio:G1SecL01/2/1' /> | <Structure load='1FJ1' size='400' frame='true' align='center' scene='Studio:G1SecL01/2/1' / caption='Outer surface protein A complex with antibody (PDB code [[1fj1]])'> | ||
<scene name='Studio:G1SecL01/2/1'>Initial Scene</scene> | <scene name='Studio:G1SecL01/2/1'>Initial Scene</scene>---<scene name='Studio:G1SecL01/2/2'>Three Loops</scene> | ||
<scene name='Studio:G1SecL01/2/2'>Three Loops</scene> | |||
LA-2 fab recognizes the three surface-exposed loops; loop1, loop 2 and loop 3 of the C-terminal domain of OspA that are on the tip of the elongated molecule most distant from the lipid-modified N terminus. Residues 203 to 220 in “loop 1“,residues 224 to 233 in “loop 2“ and residues 246 to 257 in “loop 3“are mostly effected by la-2 binding. In loop 1 residues 206 and 216 are not affected. The interactions between OspA and LA-2 include eight direct hydrogen bonds, four solvent-bridged hydrogen bonds, three ion pairs, and numerous van der Waals interactions.<ref name = "interactions">•Ding W, Huang X, Yang X, Dunn JJ, Luft BJ, Koide S, Lawson CL. Structural identification of a key protective B-cell epitope in Lyme disease antigen OspA. J Mol Biol. 2000 Oct 6;302(5):1153-64.PMID:11183781 doi:10.1006/jmbi.2000.4119 | LA-2 fab recognizes the three surface-exposed loops; loop1, loop 2 and loop 3 of the C-terminal domain of OspA that are on the tip of the elongated molecule most distant from the lipid-modified N terminus. Residues 203 to 220 in “loop 1“,residues 224 to 233 in “loop 2“ and residues 246 to 257 in “loop 3“are mostly effected by la-2 binding. In loop 1 residues 206 and 216 are not affected. The interactions between OspA and LA-2 include eight direct hydrogen bonds, four solvent-bridged hydrogen bonds, three ion pairs, and numerous van der Waals interactions.LA-2 recognition of OspA involves an induced fit mechanism where loop 1-3 conformations shift to optimize complementarity to the antigen-combining site. <ref name = "interactions">•Ding W, Huang X, Yang X, Dunn JJ, Luft BJ, Koide S, Lawson CL. Structural identification of a key protective B-cell epitope in Lyme disease antigen OspA. J Mol Biol. 2000 Oct 6;302(5):1153-64.PMID:11183781 doi:10.1006/jmbi.2000.4119 | ||
</ref> | </ref> | ||
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Although the LA-2- ospA complex induces a high reactivity of protective immune response for ''B. burgdorferi'', it lacks the broad specificity to encompass other genospecies of ''Borrelia''. In North America, Lyme borreliosis is caused by a single strain ''B.burgdorferi'', whereas in parts of Europe and Asia, a minimum of three strains, ''B. afzelli'', ''B. burgdorferi'', and ''B. garinii'' are involved in infecting humans<ref>PMID: 21217174</ref>. The lack of broad specificity in the LA-2- OspA complex is due to the presence of highly variable regions in ospA. | Although the LA-2- ospA complex induces a high reactivity of protective immune response for ''B. burgdorferi'', it lacks the broad specificity to encompass other genospecies of ''Borrelia''. In North America, Lyme borreliosis is caused by a single strain ''B.burgdorferi'', whereas in parts of Europe and Asia, a minimum of three strains, ''B. afzelli'', ''B. burgdorferi'', and ''B. garinii'' are involved in infecting humans<ref>PMID: 21217174</ref>. The lack of broad specificity in the LA-2- OspA complex is due to the presence of highly variable regions in ospA. | ||
<Structure load='1fj1' size='450' frame='true' align='right' caption=' | <Structure load='1fj1' size='450' frame='true' align='right' caption='Outer surface protein A (magenta and cyan) complex with antibody light chain (grey and pink) and heavy chain (green and yellow) (PDB code [[1fj1]]) ' | ||
scene='Insert optional scene name here' /> | scene='Insert optional scene name here' /> | ||
<scene name='G1SecL05/1fj1_chains_labeled/4'>Label All Chains</scene>---<scene name='G1SecL05/1fj1-condensed/5'>Show Only Chain E</scene> | <scene name='G1SecL05/1fj1_chains_labeled/4'>Label All Chains</scene>---<scene name='G1SecL05/1fj1-condensed/5'>Show Only Chain E</scene>---<scene name='G1SecL05/1fj1-condensed/3'>Close up view</scene> | ||
---<scene name='G1SecL05/1fj1-condensed/3'>Close up view</scene> | |||
===Trp-216=== | ===Trp-216=== | ||
One hyper-variable region is the Tryptophan amino acid residue sequence 216. Polar amino acid side chains flank the Tryptophan, and changes in such amino acids can ultimately affect the reactivity of OspA to monoclonal antibodies<ref>PMID: 7890394</ref>. Differences in side chains of amino acids on the polar surface of a helical structure surrounding the highly conserved tryptophan residue 216 can affect the reactivity of OspA. | One hyper-variable region is the Tryptophan amino acid residue sequence 216. Polar amino acid side chains flank the Tryptophan, and changes in such amino acids can ultimately affect the reactivity of OspA to monoclonal antibodies<ref>PMID: 7890394</ref>. Differences in side chains of amino acids on the polar surface of a helical structure surrounding the highly conserved tryptophan residue 216 can affect the reactivity of OspA. | ||
===Ala-208=== | ===Ala-208=== | ||
In ''B. burgdorferi'', residue 208 expresses Alanine, whereas in ''B. afzelii'', and ''B. garinii'', Glutamine is expressed. The variation in this residue is another factor, which inhibits successful antibody cross-reactivity between other strains of ''Borrelia''. LA-2 and OspA of ''B. burgdorferi'' forms a tight border when binding and this is promoted by the Alanine 208 residue. The Glutamine residue that is found in ''B. afzelii'' and ''B. garinii'' is longer and more problematic when it comes to binding<ref name = "interactions"/>. It creates a looser, more ineffective interface between the LA-2 and OspA, which conclusively makes an ineffectual vaccine. | In ''B. burgdorferi'', residue 208 expresses Alanine, whereas in ''B. afzelii'', and ''B. garinii'', Glutamine is expressed. The variation in this "first loop" residue is another factor, which inhibits successful antibody cross-reactivity between other strains of ''Borrelia''. LA-2 and OspA of ''B. burgdorferi'' forms a tight border when binding and this is promoted by the Alanine 208 residue. The Glutamine residue that is found in ''B. afzelii'' and ''B. garinii'' is longer and more problematic when it comes to binding<ref name = "interactions"/>. It creates a looser, more ineffective interface between the LA-2 and OspA, which conclusively makes an ineffectual vaccine. | ||
===Residues 217-237=== | ===Residues 217-237=== | ||
The binding of OspA and the LA-2 FAB is defined by the amino acid residue sequence 217-237, and causes nonspecific binding thus inhibiting the LA2-FAB-OspA complex binding to other species of ''Borrelia''<ref>PMID: 15864264</ref>. | This region is crucial in determining the effectiveness of the vaccine. The binding of OspA and the LA-2 FAB is defined by the amino acid residue sequence 217-237, and causes nonspecific binding thus inhibiting the LA2-FAB-OspA complex binding to other species of ''Borrelia''<ref>PMID: 15864264</ref>. | ||
==Literature References== | ==Literature References== | ||