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Diversity of T cell epitopes in Plasmodium falciparum circumsporozoite protein likely due to protein-protein interactions.

Aragam NR, Thayer KM, Nge N, Hoffman I, Martinson F, Kamwendo D, Lin FC, Sutherland C, Bailey JA, Juliano JJ - PLoS ONE (2013)

Bottom Line: Using the information from these parasite populations, structural analysis reveals that polymorphic amino acids within TH2 and TH3 colocalize to one side of the protein, surround, but do not involve, the hydrophobic pocket in CS, and predominately involve charge switches.In addition, free energy analysis shows polymorphic residues tend to be populated by energetically unfavorable amino acids.In combination, these findings suggest the diversity of T cell epitopes in CS may be primarily an evolutionary response to intermolecular interactions at the surface of the protein potentially counteracting antibody-mediated immune recognition or evolving host receptor diversity.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.

ABSTRACT
Circumsporozoite protein (CS) is a leading vaccine antigen for falciparum malaria, but is highly polymorphic in natural parasite populations. The factors driving this diversity are unclear, but non-random assortment of the T cell epitopes TH2 and TH3 has been observed in a Kenyan parasite population. The recent publication of the crystal structure of the variable C terminal region of the protein allows the assessment of the impact of diversity on protein structure and T cell epitope assortment. Using data from the Gambia (55 isolates) and Malawi (235 isolates), we evaluated the patterns of diversity within and between epitopes in these two distantly-separated populations. Only non-synonymous mutations were observed with the vast majority in both populations at similar frequencies suggesting strong selection on this region. A non-random pattern of T cell epitope assortment was seen in Malawi and in the Gambia, but structural analysis indicates no intramolecular spatial interactions. Using the information from these parasite populations, structural analysis reveals that polymorphic amino acids within TH2 and TH3 colocalize to one side of the protein, surround, but do not involve, the hydrophobic pocket in CS, and predominately involve charge switches. In addition, free energy analysis suggests residues forming and behind the novel pocket within CS are tightly constrained and well conserved in all alleles. In addition, free energy analysis shows polymorphic residues tend to be populated by energetically unfavorable amino acids. In combination, these findings suggest the diversity of T cell epitopes in CS may be primarily an evolutionary response to intermolecular interactions at the surface of the protein potentially counteracting antibody-mediated immune recognition or evolving host receptor diversity.

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Related in: MedlinePlus

Location of TH2 and TH3 epitopes in the Structure of Circumsporozoite Protein.The relative location of TH2 (blue) and TH3 (pink) are shown within the protein structure.
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pone-0062427-g005: Location of TH2 and TH3 epitopes in the Structure of Circumsporozoite Protein.The relative location of TH2 (blue) and TH3 (pink) are shown within the protein structure.

Mentions: Using the recently published crystal structure PDBID 3VDJ, we sought to conduct structural mapping of the highly mutable sites to gain insight as to how they are spatially oriented and related to one another. A surprising feature of the 3VDJ structure is its lack of resemblance to homologous domains in proteins such as thrombospondin, f-spondin and ADAMTS13, which have two antiparallel β sheets and one additional antiparallel strand, all held together by disulfide bridges [19]. The CS structure, on the other hand, features a short α-helical portion capped by a loop that folds onto the structure, and the N-terminal strand is ordered into an α-helix tethered beneath the flap by a hydrophobic stacking interaction of Trp 331 into the antiparallel β sheets. The highly mutable sites map to the αhelix, formed by the TH2 epitope, and the flap, formed by the TH3 epitope (Figure 5). Furthermore, the novel pocket created by this unusual structure is comprised of highly conserved residues. The most polymorphic residues point away from the pocket. The surface views, rendered with a probe having a radius of 1.4 angstroms, the size of a water molecule (Figure 6), show that the conserved pocket is quite large and readily accessible to solvent. Furthermore, the rear surface of the structure is highly conserved.


Diversity of T cell epitopes in Plasmodium falciparum circumsporozoite protein likely due to protein-protein interactions.

Aragam NR, Thayer KM, Nge N, Hoffman I, Martinson F, Kamwendo D, Lin FC, Sutherland C, Bailey JA, Juliano JJ - PLoS ONE (2013)

Location of TH2 and TH3 epitopes in the Structure of Circumsporozoite Protein.The relative location of TH2 (blue) and TH3 (pink) are shown within the protein structure.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646838&req=5

pone-0062427-g005: Location of TH2 and TH3 epitopes in the Structure of Circumsporozoite Protein.The relative location of TH2 (blue) and TH3 (pink) are shown within the protein structure.
Mentions: Using the recently published crystal structure PDBID 3VDJ, we sought to conduct structural mapping of the highly mutable sites to gain insight as to how they are spatially oriented and related to one another. A surprising feature of the 3VDJ structure is its lack of resemblance to homologous domains in proteins such as thrombospondin, f-spondin and ADAMTS13, which have two antiparallel β sheets and one additional antiparallel strand, all held together by disulfide bridges [19]. The CS structure, on the other hand, features a short α-helical portion capped by a loop that folds onto the structure, and the N-terminal strand is ordered into an α-helix tethered beneath the flap by a hydrophobic stacking interaction of Trp 331 into the antiparallel β sheets. The highly mutable sites map to the αhelix, formed by the TH2 epitope, and the flap, formed by the TH3 epitope (Figure 5). Furthermore, the novel pocket created by this unusual structure is comprised of highly conserved residues. The most polymorphic residues point away from the pocket. The surface views, rendered with a probe having a radius of 1.4 angstroms, the size of a water molecule (Figure 6), show that the conserved pocket is quite large and readily accessible to solvent. Furthermore, the rear surface of the structure is highly conserved.

Bottom Line: Using the information from these parasite populations, structural analysis reveals that polymorphic amino acids within TH2 and TH3 colocalize to one side of the protein, surround, but do not involve, the hydrophobic pocket in CS, and predominately involve charge switches.In addition, free energy analysis shows polymorphic residues tend to be populated by energetically unfavorable amino acids.In combination, these findings suggest the diversity of T cell epitopes in CS may be primarily an evolutionary response to intermolecular interactions at the surface of the protein potentially counteracting antibody-mediated immune recognition or evolving host receptor diversity.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.

ABSTRACT
Circumsporozoite protein (CS) is a leading vaccine antigen for falciparum malaria, but is highly polymorphic in natural parasite populations. The factors driving this diversity are unclear, but non-random assortment of the T cell epitopes TH2 and TH3 has been observed in a Kenyan parasite population. The recent publication of the crystal structure of the variable C terminal region of the protein allows the assessment of the impact of diversity on protein structure and T cell epitope assortment. Using data from the Gambia (55 isolates) and Malawi (235 isolates), we evaluated the patterns of diversity within and between epitopes in these two distantly-separated populations. Only non-synonymous mutations were observed with the vast majority in both populations at similar frequencies suggesting strong selection on this region. A non-random pattern of T cell epitope assortment was seen in Malawi and in the Gambia, but structural analysis indicates no intramolecular spatial interactions. Using the information from these parasite populations, structural analysis reveals that polymorphic amino acids within TH2 and TH3 colocalize to one side of the protein, surround, but do not involve, the hydrophobic pocket in CS, and predominately involve charge switches. In addition, free energy analysis suggests residues forming and behind the novel pocket within CS are tightly constrained and well conserved in all alleles. In addition, free energy analysis shows polymorphic residues tend to be populated by energetically unfavorable amino acids. In combination, these findings suggest the diversity of T cell epitopes in CS may be primarily an evolutionary response to intermolecular interactions at the surface of the protein potentially counteracting antibody-mediated immune recognition or evolving host receptor diversity.

Show MeSH
Related in: MedlinePlus