Structural and functional insights from detailed computational analysis of Plasmodium repetome

Eukaryotic proteomes harbour tandem repeats (TRs) of amino acids that may play critical roles in the biology of organisms. While a few TRs have been shown to contribute to protein structure and function, information about the vast majority of repeat regions remains obscure. This article reports a detailed computational analysis of the repeat content of different Plasmodium species proteomes, identifying P. falciparum (Pf) and P. vivax to be exceptionally rich in TR regions. P. falciparum 'repetome' was found to carry longer TRs, which were majorly present in exported parasite proteins, important for pathogen survival and immune evasion. Short and intermediate TRs of P. falciparum showed a bias towards Asparagine usage, suggesting an evolutionary outcome influenced by replication slippage and positive selection. Gene ontology analysis revealed the largest proportion of TR containing Pf proteins to be involved in binding nucleic acids, proteins and other small molecules. Surprisingly, the Plasmodium specific variable surface antigen (VSA) families known to have roles in immune evasion and cytoadherence were found to contain low repeat content. Our analysis also revealed that all the TR containing VSAs were sero-reactive, where several antigenic peptides were present within the repeats. Three-dimensional structure predictions of TR regions showed several repeats to form ordered super-secondary conformations, which are often reported to facilitate intermolecular interactions. Overall, this comprehensive study provides glimpses into the probable roles of TRs in Plasmodium biology and also suggests a novel method for understanding protein function via characterization of repetitive sequences.