User:Marvin O'Neal/OspC: Difference between revisions

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This conceptual model characterizing the ecological interactions between vertebrate host community and distribution frequency of invasive oMGs determine the cases of human Lyme disease. The principal natural reservoir host for the epidemic of Lyme disease in northeastern and central United States is the presence of only white-footed mice (''Peromyscus leucopus'') population, which has both high frequency distribution in all four human infectious oMGs and high transmission probabilities of oMGs A, B, I and K<ref name="Distribution frequency of particular oMGs">PMID:16606995</ref>. In addition, ticks are least likely to parasitize on inefficient reservoir hosts, thereby increasing high infection prevalence in the tick population, which enhances the risk of exposure of Lyme disease in humans. Therefore, dilution-effect model proposes that maintaining high diversity of vertebrate host community may dilute the power of white-footed mouse by increasing the degree of specialization of ticks on inefficient hosts. This model strongly demonstrates the relationship between species diversity in the community of hosts and the risk of human exposure to Lyme disease. These ecological driving forces described in the model are useful tools in predicting the prevalence and risk of human Lyme disease.
This conceptual model characterizing the ecological interactions between vertebrate host community and distribution frequency of invasive oMGs determine the cases of human Lyme disease. The principal natural reservoir host for the epidemic of Lyme disease in northeastern and central United States is the presence of only white-footed mice (''Peromyscus leucopus'') population, which has both high frequency distribution in all four human infectious oMGs and high transmission probabilities of oMGs A, B, I and K<ref name="Distribution frequency of particular oMGs">PMID:16606995</ref>. In addition, ticks are least likely to parasitize on inefficient reservoir hosts, thereby increasing high infection prevalence in the tick population, which enhances the risk of exposure of Lyme disease in humans. Therefore, dilution-effect model proposes that maintaining high diversity of vertebrate host community may dilute the power of white-footed mouse by increasing the degree of specialization of ticks on inefficient hosts. This model strongly demonstrates the relationship between species diversity in the community of hosts and the risk of human exposure to Lyme disease. These ecological driving forces described in the model are useful tools in predicting the prevalence and risk of human Lyme disease.


== Structure of outer surface protein C (OspC) ==
==Primary and Secondary structure of OspC==
{{STRUCTURE_1ggq| PDB=1ggq | SCENE=Studio:G4SecL04/Dimer_with_mg/1}}
{{STRUCTURE_1ggq| PDB=1ggq | SCENE=Studio:G4SecL04/Dimer_with_mg/1}}
'''Primary Structure'''


The model presented is B31 strain (residues 38-201), which is also known as oMG A. This is one of four invasive oMGs that are responsible for systematic Lyme disease. In crystal structure, OspC exists as a  
The model presented is B31 strain (residues 38-201), which is also known as oMG A. This is one of four invasive oMGs that are responsible for systematic Lyme disease. In crystal structure, OspC exists as a  
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and six  
and six  
<scene name='Studio:G4SecL04/Random_coils/2' target='1'>random coils</scene>
<scene name='Studio:G4SecL04/Random_coils/2' target='1'>random coils</scene>
. The N and C termini at the membrane proximal end of two long alpha helices,  
. The '''N and C termini''' at the membrane proximal end of two long alpha helices,  
<scene name='Studio:G4SecL04/N_and_c_termini_with_helix/1' target='1'>α1 (residues 38-76) and α5 (residues 170-201)</scene> are in close proximity to each other.  At the membrane distal end, there are three remaining alpha helices,  
<scene name='Studio:G4SecL04/N_and_c_termini_with_helix/1' target='1'>α1 (residues 38-76) and α5 (residues 170-201)</scene> are in close proximity to each other.  At the membrane distal end, there are three remaining alpha helices,  
<scene name='Studio:G4SecL04/Alpha_2/1' target='1'>α2 (residues 95-112)</scene>,  
<scene name='Studio:G4SecL04/Alpha_2/1' target='1'>α2 (residues 95-112)</scene>,  
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<scene name='Studio:G4SecL04/Beta_02/1' target='1'>β2 (residues 88-89)</scene> are formed. Based on the alignment of all oMGs, towards the membrane proximal end, the surface-exposed residues on α1 and α5 are highly conserved, resulting positively charged surface. Other than those on helices, α1 and α5, the surface-exposed residues on the remaining regions of OspC molecule are variable.
<scene name='Studio:G4SecL04/Beta_02/1' target='1'>β2 (residues 88-89)</scene> are formed. Based on the alignment of all oMGs, towards the membrane proximal end, the surface-exposed residues on α1 and α5 are highly conserved, resulting positively charged surface. Other than those on helices, α1 and α5, the surface-exposed residues on the remaining regions of OspC molecule are variable.


'''Evolutionary Conservation of OspC'''
==Evolutionary Conservation of OspC==
 
Since OspC locus is the most variable gene, the sequence alignment of all oMGs reveals that towards the membrane proximal end, the surface-exposed residues on α1 and α5 are highly conserved, resulting positively charged surface. Other than those on helices, α1 and α5, the surface-exposed residues on the remaining regions of OspC molecule are variable.


'''Model of OspC'''
Since OspC locus is the most variable gene, the sequence alignment of all oMGs reveals that towards the membrane proximal end, the surface-exposed residues on α1 and α5 are highly conserved, resulting positively charged surface. Other than those on helices, α1 and α5, the surface-exposed residues on the remaining regions of OspC molecule are variable <ref>PMID: 11139584 </ref>.


At the membrane distal region, the six loop regions, including two β-strands illustrates the most antigenic sites of OspC due to the presence of variable surface-exposed residues among OspC isolates. <ref>Earnhart C, LeBlanc D, Alix K, Desrosiers D, Radolf J, and Marconi R. 2010. Identification of residues within ligand-binding domain 1 (LBD1) of the ''Borrelia burgdorferi'' OspC protein required for function in the mammalian environment. Molecular Microbiology 76(2): 393-408. [http://dx.crossref.org/10.1111%2Fj.1365-2958.2010.07103.x DOI: 10.1111/j.1365-2958.2010.07103.x]</ref>. However, among these variable regions, the outer surface-exposed residues connecting the helices α1 and α2, forming the loops, L1 (residues 74-78), L2 (residues 81-87), L3 (residues 90-93) and two short beta strands, β1 and β2 and also L5 (residues 146-150) are more highly variable than those present in the loops, L4 (residues 115-119) and L6 (residues 161-169). Consequently, the surface potential of red region that projects away from the membrane is negatively charged and mainly involved in the protein-protein or protein-ligand interactions (Eicken et al. 2001). Only four types of oMGs (A, B, I and K), whose surface potential in red region is highly negative relative to non-invasive one plays a major role in pathogenesis of human Lyme disease (Kumaran 2001). The residue, <scene name='Studio:G4SecL04/82nd_residue/1'>His82</scene>, located on the red region at the membrane distal end is unique that the replacement of other residues except His82, Lys82, Gln82, which are present only in four invasive oMGs enhances the possibility of turning invasive strains to non-invasive one. Thus, the stronger the electrostatic potential on red region, the higher the chance for OspC to bind with positively charged host ligands. Therefore, the alternation of an amino acid residue at the 82nd position on red region not only demonstrates OspC polymorphism, but also points out the probability for turning invasive strains to non-invasive strains <ref>Kumaran D, Eswaramoorthy S, Luft B, Koide S, Dunn J, Lawson C, and Swaminathan S. 2001. Crystal Structure of Outer Surface Protein C (OspC) from the Lyme Disease Spirochete, ''Borrelia burgdorferi''. The EMBO Journal 20(5): 971-978. [http://dx.crossref.org/10.1093%2Femboj%2F20.5.971 DOI:  10.1093/emboj/20.5.971]</ref>.
==Model of OspC==


At the membrane distal region, the six loop regions, including two β-strands illustrates the
<scene name='Studio:G4SecL04/Major_antigenic_site/1' target='1'>most antigenic sites</scene>
of OspC due to the presence of variable surface-exposed residues among OspC isolates. <ref>Earnhart C, LeBlanc D, Alix K, Desrosiers D, Radolf J, and Marconi R. 2010. Identification of residues within ligand-binding domain 1 (LBD1) of the ''Borrelia burgdorferi'' OspC protein required for function in the mammalian environment. Molecular Microbiology 76(2): 393-408. [http://dx.crossref.org/10.1111%2Fj.1365-2958.2010.07103.x DOI: 10.1111/j.1365-2958.2010.07103.x]</ref>. However, among these variable regions, the outer surface-exposed residues connecting the helices α1 and α2, forming the loops,
<scene name='Studio:G4SecL04/L1/3' target='1'>L1 (residues 74-78)</scene>,
<scene name='Studio:G4SecL04/L2/2' target='1'>L2 (residues 81-87)</scene>, 
<scene name='Studio:G4SecL04/L3/2' target='1'>L3 (residues 90-93)</scene> and two short beta strands, β1 and β2, and also
<scene name='Studio:G4SecL04/L5/2' target='1'>L5 (residues 146-150)</scene>
are more highly variable than those present in the loops,
<scene name='Studio:G4SecL04/L4/1' target='1'>L4 (residues 115-119)</scene> and
<scene name='Studio:G4SecL04/L6/1'>L6 (residues 161-169)</scene>. Consequently, the surface potential of red region that projects away from the membrane is negatively charged and mainly involved in the protein-protein or protein-ligand interactions (Eicken et al. 2001). Only four types of oMGs (A, B, I and K), whose surface potential in red region is highly negative relative to non-invasive one plays a major role in pathogenesis of human Lyme disease (Kumaran 2001). The residue,
<scene name='Studio:G4SecL04/82/1' target='1'>His82</scene>, located on the red region at the membrane distal end is unique that the replacement of other residues except His82, Lys82, Gln82, which are present only in four invasive oMGs enhances the possibility of turning invasive strains to non-invasive one. Thus, the stronger the electrostatic potential on red region, the higher the chance for OspC to bind with positively charged host ligands. Therefore, the alternation of an amino acid residue at the 82nd position on red region not only demonstrates OspC polymorphism, but also points out the probability for turning invasive strains to non-invasive strains <ref>Kumaran D, Eswaramoorthy S, Luft B, Koide S, Dunn J, Lawson C, and Swaminathan S. 2001. Crystal Structure of Outer Surface Protein C (OspC) from the Lyme Disease Spirochete, ''Borrelia burgdorferi''. The EMBO Journal 20(5): 971-978. [http://dx.crossref.org/10.1093%2Femboj%2F20.5.971 DOI:  10.1093/emboj/20.5.971]</ref>.


==References==  
==References==  


<references />
<references />
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