Hypervariability within the Rifin, Stevor and Pfmc-2TM superfamilies in Plasmodium falciparum

Abstract

The human malaria parasite, Plasmodium falciparum, possesses a broad repertoire of proteins that are proposed to be trafficked to the erythrocyte cytoplasm or surface, based upon the presence within these proteins of a Pexel/VTS erythrocyte-trafficking motif. This catalog includes large families of predicted 2 transmembrane (2TM) proteins, including the Rifin, Stevor and Pfmc-2TM superfamilies, of which each possesses a region of extensive sequence diversity across paralogs and between isolates that is confined to a proposed surface-exposed loop on the infected erythrocyte. Here we express epitope-tagged versions of the 2TM proteins in transgenic NF54 parasites and present evidence that the Stevor and Pfmc-2TM families are exported to the erythrocyte membrane, thus supporting the hypothesis that host immune pressure drives antigenic diversity within the loop. An examination of multiple P.falciparum isolates demonstrates that the hypervariable loop within Stevor and Pfmc-2TM proteins possesses sequence diversity across isolate boundaries. The Pfmc-2TM genes are encoded within large amplified loci that share profound nucleotide identity, which in turn highlight the divergences observed within the hypervariable loop. The majority of Pexel/VTS proteins are organized together within sub-telomeric genome neighborhoods, and a mechanism must therefore exist to differentially generate sequence diversity within select genes, as well as within highly defined regions within these genes.

Plasmodium falciparum STEVOR phosphorylation regulates host erythrocyte deformability enabling malaria parasite transmission

“…We further confirmed these observations in 22-hpi asexual stages before endogenous expression of STEVOR. 16,30,31 At these stages, overexpression of the full copy of STEVOR in the Full-Ty1 line substantially increased the retention rates compared with the control line (78% vs 51.9%, P 5 0), whereas the retention rates of the Trunc-Ty1 line were at the same level as the control line (54.9% vs 51.9%, P 5 .9; Figure 1E-G). Altogether, these results indicate that STEVOR-mediated rigidity of infected erythrocytes is dependent on the C-terminal domain in both asexual and gametocytes stages.…”

“…6 The stevor multicopy gene family is 1 of the 3 major families of variant genes in P falciparum, and comprises 35 genes that are clonally expressed. [14][15][16] The encoded STEVOR proteins exhibit a semiconserved N-terminal domain and a central variable domain exposed on the erythrocyte surface, whereas the conserved C-terminal domain is cytoplasmic. 17,18 Besides their role in invasion, adhesion, and rosetting in asexual stages, [19][20][21][22] STEVOR proteins have been shown to impact the deformability of the infected erythrocyte in mature asexual parasites and immature sexual stages.…”

Transcriptional variation in the malaria parasitePlasmodium falciparum

“…Other P. falciparum gene families also show clonally variant expression, including gene families encoding proteins exported to the erythrocyte surface, and families linked to erythrocyte invasion. Variant expression of these gene families may also play a role in immune evasion (Cortés et al 2007;Lavazec et al 2007;Petter et al 2007;Cortés 2008;Scherf et al 2008;Gomez-Escobar et al 2010).…”

Maurer's clefts, the enigma of Plasmodium falciparum

“…This virulence factor is transported via the Maurer's clefts at which it transiently localizes. Other proteins destined to the erythrocyte membrane [such as RIFINs (39,(52)(53)(54)(55)(56)(57), STEVOR (58-62), PfMC-2TM (60,63,64), FIKK kinase (65)(66)(67), and probably members of the CLAG family] also pass through the Maurer's clefts on their way to the erythrocyte membrane, again highlighting the tremendous significance of these structures.…”