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

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.

A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase

“…Reactivity of GPIHBP1 Autoantibodies. Due to their low sequence complexity and paucity of hydrophobic residues, IDRs are generally poor ligands for MHC class II and are likely to escape adaptive immune responses (37,38). In keeping with our SAXS data, the first 35 residues of human GPIHBP1 are predicted to be highly disordered, translating into a low predicted affinity for MHC class II (Fig.…”

Disordered epitopes as peptide vaccines

“…Thus, organisms that live in diverse or highly variable environments tend to have highly disordered proteomes, reflecting the need for sophisticated regulatory mechanisms to survive such environmental diversity. As a result, disordered proteins are particularly abundant in a range of pathogenic organisms, and in some viruses, which must survive diverse and often hostile host environments. In these contexts, disordered proteins play important roles in host‐pathogen interactions, and accordingly, disordered proteins are often exposed to the host immune system .…”

“…As a result, disordered proteins are particularly abundant in a range of pathogenic organisms, and in some viruses, which must survive diverse and often hostile host environments. In these contexts, disordered proteins play important roles in host‐pathogen interactions, and accordingly, disordered proteins are often exposed to the host immune system . Even amongst bacteria, which have significantly more ordered proteomes than eukaryotic species, many proteins involved in pathogenic effector mechanisms appear to be disordered …”

Expansion of Lysine-rich Repeats in Plasmodium Proteins Generates Novel Localization Sequences That Target the Periphery of the Host Erythrocyte

“…Some repeating sequences appear to be under immune selection (30), and many are highly antigenic (31); it has been proposed that this may allow the parasite to evade the host immune system by diverting B-cell responses toward non-protective epitopes (32) or promoting an inferior T-cell-independent maturation of B-cells (33, 34). Such general roles for tandemly repeating sequences may explain their broad distribution in parasite proteins.…”