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Insights into the Immunological Properties of Intrinsically Disordered Malaria Proteins Using Proteome Scale Predictions.

Guy AJ, Irani V, MacRaild CA, Anders RF, Norton RS, Beeson JG, Richards JS, Ramsland PA - PLoS ONE (2015)

Bottom Line: The development of an effective malaria vaccine remains as a major challenge with the potential to significantly reduce morbidity and mortality.Presentation of peptides by MHC molecules plays an important role in adaptive immune responses, and we show that IDP regions are predicted to contain relatively few MHC class I and II binding peptides owing to inherent differences in amino acid composition compared to structured domains.Tandem repeat regions and non-synonymous single nucleotide polymorphisms were found to be strongly associated with regions of disorder.

View Article: PubMed Central - PubMed

Affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne, Australia; Department of Immunology, Monash University, Melbourne, Australia.

ABSTRACT
Malaria remains a significant global health burden. The development of an effective malaria vaccine remains as a major challenge with the potential to significantly reduce morbidity and mortality. While Plasmodium spp. have been shown to contain a large number of intrinsically disordered proteins (IDPs) or disordered protein regions, the relationship of protein structure to subcellular localisation and adaptive immune responses remains unclear. In this study, we employed several computational prediction algorithms to identify IDPs at the proteome level of six Plasmodium spp. and to investigate the potential impact of protein disorder on adaptive immunity against P. falciparum parasites. IDPs were shown to be particularly enriched within nuclear proteins, apical proteins, exported proteins and proteins localised to the parasitophorous vacuole. Furthermore, several leading vaccine candidates, and proteins with known roles in host-cell invasion, have extensive regions of disorder. Presentation of peptides by MHC molecules plays an important role in adaptive immune responses, and we show that IDP regions are predicted to contain relatively few MHC class I and II binding peptides owing to inherent differences in amino acid composition compared to structured domains. In contrast, linear B-cell epitopes were predicted to be enriched in IDPs. Tandem repeat regions and non-synonymous single nucleotide polymorphisms were found to be strongly associated with regions of disorder. In summary, immune responses against IDPs appear to have characteristics distinct from those against structured protein domains, with increased antibody recognition of linear epitopes but some constraints for MHC presentation and issues of polymorphisms. These findings have major implications for vaccine design, and understanding immunity to malaria.

No MeSH data available.


Related in: MedlinePlus

Predicted protein disorder for a number of leading P. falciparum vaccine candidates.Disorder predictions were performed using DISOPRED3. A disorder score above 0.5 is indicative of a disordered region (dashed line). All sequences used were from the P. falciparum 3D7 strain.
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pone.0141729.g003: Predicted protein disorder for a number of leading P. falciparum vaccine candidates.Disorder predictions were performed using DISOPRED3. A disorder score above 0.5 is indicative of a disordered region (dashed line). All sequences used were from the P. falciparum 3D7 strain.

Mentions: We considered disorder at both a per-proteome level (i.e. the number of residues across the proteome that fall within disordered regions; expressed as a proportion of residues for the entire proteome) and at a per-protein level (the percentage of predicted disordered residues for each protein). IDPs constituted a significant proportion of the proteomes of the six Plasmodium species assessed. On a per-proteome basis, the proportions of the proteomes predicted to be disordered were as follows: P. falciparum 32.7%, P. vivax 33.2%, P. knowlesi 30.6%, P. berghei 26.7%, P. chabaudi 27.6% and P. yoelii 27.5%. The median degree of disorder per-protein for P. falciparum was 15.5% (IQR = 6.7–31.6%; Fig 2A). No significant differences between the proportion of disorder per-protein were observed among any of the Plasmodium spp. tested (p > 0.05, Kruskal-Wallis rank sum test). After combining the results for the six Plasmodium spp. tested, the median disorder per-protein was 15.1% (IQR = 7.0–29.7%). Several leading P. falciparum vaccine candidates were also assessed to determine the proportion of these proteins that are disordered. There was a significant proportion of disorder among many of these proteins including: 1) pre-erythrocytic antigens: CSP (75.1%), LSA1 (40.6%), TRAP (47.7%); 2) erythrocytic stage antigens: MSP1 (59.1%), MSP2 (72.4%), MSP3 (52.3%), EBA175 (46.6%), AMA1 (21.5%), RESA (50.5%), Rh5 (8.0%), GLURP (95.4%), SERA5 (29.1%); and 3) sexual stage antigens: Pfs25 (5.5%) and Pfs230 (21.3%). The distribution of this disorder is shown for some selected examples, highlighting the heterogeneity of disorder amongst leading vaccine candidates, and demonstrating that vast regions of some these proteins may be almost entirely disordered (Fig 3).


Insights into the Immunological Properties of Intrinsically Disordered Malaria Proteins Using Proteome Scale Predictions.

Guy AJ, Irani V, MacRaild CA, Anders RF, Norton RS, Beeson JG, Richards JS, Ramsland PA - PLoS ONE (2015)

Predicted protein disorder for a number of leading P. falciparum vaccine candidates.Disorder predictions were performed using DISOPRED3. A disorder score above 0.5 is indicative of a disordered region (dashed line). All sequences used were from the P. falciparum 3D7 strain.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4626106&req=5

pone.0141729.g003: Predicted protein disorder for a number of leading P. falciparum vaccine candidates.Disorder predictions were performed using DISOPRED3. A disorder score above 0.5 is indicative of a disordered region (dashed line). All sequences used were from the P. falciparum 3D7 strain.
Mentions: We considered disorder at both a per-proteome level (i.e. the number of residues across the proteome that fall within disordered regions; expressed as a proportion of residues for the entire proteome) and at a per-protein level (the percentage of predicted disordered residues for each protein). IDPs constituted a significant proportion of the proteomes of the six Plasmodium species assessed. On a per-proteome basis, the proportions of the proteomes predicted to be disordered were as follows: P. falciparum 32.7%, P. vivax 33.2%, P. knowlesi 30.6%, P. berghei 26.7%, P. chabaudi 27.6% and P. yoelii 27.5%. The median degree of disorder per-protein for P. falciparum was 15.5% (IQR = 6.7–31.6%; Fig 2A). No significant differences between the proportion of disorder per-protein were observed among any of the Plasmodium spp. tested (p > 0.05, Kruskal-Wallis rank sum test). After combining the results for the six Plasmodium spp. tested, the median disorder per-protein was 15.1% (IQR = 7.0–29.7%). Several leading P. falciparum vaccine candidates were also assessed to determine the proportion of these proteins that are disordered. There was a significant proportion of disorder among many of these proteins including: 1) pre-erythrocytic antigens: CSP (75.1%), LSA1 (40.6%), TRAP (47.7%); 2) erythrocytic stage antigens: MSP1 (59.1%), MSP2 (72.4%), MSP3 (52.3%), EBA175 (46.6%), AMA1 (21.5%), RESA (50.5%), Rh5 (8.0%), GLURP (95.4%), SERA5 (29.1%); and 3) sexual stage antigens: Pfs25 (5.5%) and Pfs230 (21.3%). The distribution of this disorder is shown for some selected examples, highlighting the heterogeneity of disorder amongst leading vaccine candidates, and demonstrating that vast regions of some these proteins may be almost entirely disordered (Fig 3).

Bottom Line: The development of an effective malaria vaccine remains as a major challenge with the potential to significantly reduce morbidity and mortality.Presentation of peptides by MHC molecules plays an important role in adaptive immune responses, and we show that IDP regions are predicted to contain relatively few MHC class I and II binding peptides owing to inherent differences in amino acid composition compared to structured domains.Tandem repeat regions and non-synonymous single nucleotide polymorphisms were found to be strongly associated with regions of disorder.

View Article: PubMed Central - PubMed

Affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne, Australia; Department of Immunology, Monash University, Melbourne, Australia.

ABSTRACT
Malaria remains a significant global health burden. The development of an effective malaria vaccine remains as a major challenge with the potential to significantly reduce morbidity and mortality. While Plasmodium spp. have been shown to contain a large number of intrinsically disordered proteins (IDPs) or disordered protein regions, the relationship of protein structure to subcellular localisation and adaptive immune responses remains unclear. In this study, we employed several computational prediction algorithms to identify IDPs at the proteome level of six Plasmodium spp. and to investigate the potential impact of protein disorder on adaptive immunity against P. falciparum parasites. IDPs were shown to be particularly enriched within nuclear proteins, apical proteins, exported proteins and proteins localised to the parasitophorous vacuole. Furthermore, several leading vaccine candidates, and proteins with known roles in host-cell invasion, have extensive regions of disorder. Presentation of peptides by MHC molecules plays an important role in adaptive immune responses, and we show that IDP regions are predicted to contain relatively few MHC class I and II binding peptides owing to inherent differences in amino acid composition compared to structured domains. In contrast, linear B-cell epitopes were predicted to be enriched in IDPs. Tandem repeat regions and non-synonymous single nucleotide polymorphisms were found to be strongly associated with regions of disorder. In summary, immune responses against IDPs appear to have characteristics distinct from those against structured protein domains, with increased antibody recognition of linear epitopes but some constraints for MHC presentation and issues of polymorphisms. These findings have major implications for vaccine design, and understanding immunity to malaria.

No MeSH data available.


Related in: MedlinePlus