Antigenic variation in Plasmodium falciparum : understanding the RIFIN protein family

RIFIN proteins are variable surface antigens, which have a central role in the survival and virulence of the malaria parasite Plasmodium falciparum. Antigenic variation is a mean for these parasites to avoid clearance by the host s immune system. However, this is often a secondary function to the main role of these proteins. In the case of RIFIN, P. falciparum s largest multicopy protein family, the main functions remain unknown. In order to elucidate a protein s function, it is crucial to understand its basic properties, including the structure of the protein family, their localization and the protein s topology.

Through different methods, we have strived to simplify the RIFIN protein family into manageable entities. We have started with a simple classification of RIFIN proteins into meaningful sub-groups. We have predicted that these sub-groups are functionally distinct, although they probably share a related function.

We then designed RSPred, an automatic method, based on hidden Markov models and a sorting program, to detect and classify RIFIN and STEVOR sequences according to their sub-group.

Finally, using an in vitro method to determine protein topology, we have analyzed both A-RIFIN and B-RIFIN proteins for their number of transmembrane segments and their topologies. We show that both protein groups have a signal sequence targeting them to lipid bilayers and only one transmembrane domain. They both share a common topology where the bulk of the protein is exposed to the extracellular environment.

With the current knowledge of RIFIN protein localizations, as well as the loss of expression of A-RIFIN but not B-RIFIN proteins in a splenectomized patient, it seems increasingly clear that B-RIFIN proteins are good targets for future studies, to decipher the functions of these variable proteins.

List of scientific papers

I. Joannin N, Abhiman S, Sonnhammer EL, Wahlgren M. (2008). "Sub-grouping and sub-functionalization of the RIFIN multi-copy protein family." BMC Genomics 15: 19
https://pubmed.ncbi.nlm.nih.gov/18197962

II. Joannin N*, Kallberg Y*, Wahlgren M, Persson B (2010). "RSpred, a set of hidden Markov models to detect and classify the RIFIN and STEVOR proteins of Plasmodium falciparum" (Submitted)

III. Joannin N, Enquist K, Wahlgren M, von Heijne G, Nilsson I (2010). "RIFIN topology: a new perspective on Plasmodium falciparum variable surface antigens" (Manuscript)

IV. Hayes CN, Diez D, Joannin N, Honda W, Kanehisa M, Wahlgren M, Wheelock CE, Goto S. (2008). "varDB: a pathogen-specific sequence database of protein families involved in antigenic variation." Bioinformatics 24: 2564-2565
https://pubmed.ncbi.nlm.nih.gov/18776192