Abstract
The var gene encoded hyper-variable Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family mediates cytoadhesion of infected erythrocytes to human endothelium. Antibodies blocking cytoadhesion are important mediators of malaria immunity acquired by endemic populations. The development of a PfEMP1 based vaccine mimicking natural acquired immunity depends on a thorough understanding of the evolved PfEMP1 diversity, balancing antigenic variation against conserved receptor binding affinities. This study redefines and reclassifies the domains of PfEMP1 from seven genomes. Analysis of domains in 399 different PfEMP1 sequences allowed identification of several novel domain classes, and a high degree of PfEMP1 domain compositional order, including conserved domain cassettes not always associated with the established group A–E division of PfEMP1. A novel iterative homology block (HB) detection method was applied, allowing identification of 628 conserved minimal PfEMP1 building blocks, describing on average 83% of a PfEMP1 sequence. Using the HBs, similarities between domain classes were determined, and Duffy binding-like (DBL) domain subclasses were found in many cases to be hybrids of major domain classes. Related to this, a recombination hotspot was uncovered between DBL subdomains S2 and S3. The VarDom server is introduced, from which information on domain classes and homology blocks can be retrieved, and new sequences can be classified. Several conserved sequence elements were found, including: (1) residues conserved in all DBL domains predicted to interact and hold together the three DBL subdomains, (2) potential integrin binding sites in DBLα domains, (3) an acylation motif conserved in group A var genes suggesting N-terminal N-myristoylation, (4) PfEMP1 inter-domain regions proposed to be elastic disordered structures, and (5) several conserved predicted phosphorylation sites. Ideally, this comprehensive categorization of PfEMP1 will provide a platform for future studies on var/PfEMP1 expression and function.
Highlights
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates adhesion of infected erythrocytes (IE) to various host cells on the vascular lining, during the blood stage of malaria infection [1,2]
DBLf had high similarity to DBLb, most significantly in the subdomain 1 (S1) subdomain, and DBLd was very reminiscent of the DBLc in the N-terminal, some sequences were even identical on the homology block level (Figure 6g, h, j, and k)
The classification is a result of a phylogenetic approximation of the different evolutionary histories of the domain sequence blocks, identification of conserved PfEMP1 domain architectures was possible
Summary
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates adhesion of infected erythrocytes (IE) to various host cells on the vascular lining, during the blood stage of malaria infection [1,2]. Var 59 UTR sequences can be divided into upstream sequence (UPS) classes A, B, C or E. These UPS classes correlate with chromosomal position of the genes, as well as domain complexity of the encoded PfEMP1 [10,11]. Subtelomeric UPSA and UPSB genes are oriented tail to tail (39 to 39), while central UPSC genes are oriented head to tail in a tandem repeat manner [12], which has lead to the definition of group A, B and C var/PfEMP1, and two intermediate groups B/A and B/C, that contain var/PfEMP1 with chromosomal position or domain composition different from that predicted from their UPS class. Var2csa is unique as it has a unique UPSE, encodes unique Duffy binding-like (DBL) domains, as well as a distinct acidic terminal segment (ATS) [17]
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