The domain on the mouse Duffy protein for Plasmodium yoelii binding and invasion to mouse erythrocytes

Erythrocyte invasion by malaria parasites is a multi-step process requiring specific molecular interactions between merozoites and erythrocyte surface receptors. Human Duffy blood group protein is the receptor for Plasmodium vivax merozoite invasion to red blood cells. The cognate parasite ligand for Duffy protein is a 135 kDa Duffy binding protein (DBP). Previously, we defined the domain on the N-terminus of human Duffy protein required for DBP binding and showed that a 35-mer N-terminal peptide inhibited DBP binding to Duffy positive red cells in vitro. There is no efficient in vitro culture system or small animal model to study P. vivax ligand binding and invasion to red blood cells. Plasmodium yoelii is frequently used to study the interaction between host receptors and parasite ligands. Similar to human parasite P. vivax, rodent malaria parasite P. yoelii also uses Duffy protein on mouse RBCs for invasion. However, the domain on the mouse Duffy for P. yoelii binding is not known. In this communication, using a mouse model, we show that an antibody against the N-terminus of mouse Duffy protein inhibited P. yoelii invasion in the mouse. In addition, by using small peptides from the N-terminal exocellular domain, we defined the domain on the Duffy protein for P. yoelii binding and invasion to mouse erythrocytes. Our results also indicated that small peptides from the host receptor could act as decoy receptors and may be utilized as potential antimalarial drugs.     

Identification of glycosaminoglycan binding domains in Plasmodium falciparum erythrocyte membrane protein 1 of a chondroitin sulfate A-adherent parasite

Accumulation of Plasmodium falciparum-infected erythrocytes in the placenta is a key feature of maternal malaria. This process is mediated in part by the parasite ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1) at the surface of the infected erythrocyte interacting with the host receptor chondroitin sulfate A (CSA) on the placental lining. We have localized CSA binding activity to two adjacent domains in PfEMP1 of an adherent parasite line and shown the presence of at least three active glycosaminoglycan binding sites. A putative CSA binding sequence was identified in one domain, but nonlinear binding motifs are also likely to be present, since binding activity in the region was shown to be dependent on conformation. Characterization of this binding region provides an opportunity to investigate further its potential as a target for antiadhesion therapy.     

Differences in erythrocyte receptor specificity of different parts of the Plasmodium falciparum reticulocyte binding protein homologue 2a

The Plasmodium falciparum reticulocyte-binding-like protein homologue (RH) and erythrocyte binding-like (EBL) protein families play important roles during invasion, though their exact roles are not clear. Both EBL and RH proteins are thought to directly bind different receptors on the surface of the erythrocyte, and the binding properties for a number of EBLs and RHs have been described. While P. falciparum RH1 (PfRH1) and PfRH4 have been shown to act directly in two alternative invasion pathways used by merozoites, the functions of PfRH2a and PfRH2b during invasion are less defined. Here, using monoclonal antibodies raised against a unique region of PfRH2a, we show that PfRH2a moves from the rhoptry neck to the moving junction during merozoite invasion. The movement of PfRH2a to the junction is independent of the invasion pathway used by the merozoite, suggesting an additional function of the protein that is independent of receptor binding. We further show that PfRH2a is processed both in the schizont and during invasion, resulting in proteins with different erythrocyte binding properties. Our findings suggest that PfRH2a and, most likely, the other members of the RH family, depending on their processing stage, can engage different receptors at different stages of the invasion process.     

Mapping the binding site for gossypol-like inhibitors of Plasmodium falciparum lactate dehydrogenase

Gossypol is a di-sesquiterpene natural-product in the form of a functionalised binaphthyl and is isolated from cotton plants. The compound has long been known to exhibit anti-malarial and other biological activities. Previous studies have indicated that compounds of this type target Plasmodium falciparum lactate dehydrogenase (pfLDH), an essential enzyme for energy generation within the parasite. In this study, we report that simple naphthalene-based compounds, the core of the gossypol structure, exhibit weak inhibition of the parasite lactate dehydrogenase. Crystal structures of the complexes formed by binding of these naphthalene-based compounds to their target enzyme have been used to delineate the molecular features likely to form the gossypol binding site. Two modes of binding are observed: one overlapping the pyruvate but not the co-factor site, the other bridging the binding sites for the co-factor nicontinamide group and pyruvate substrate. This latter site encompasses molecular features unique to Plasmodium forms of LDH and is likely to represent the mode of binding for gossypol derivatives that show selectivity for the parasite enzymes. We also report a substrate analogue that unexpectedly binds within the adenine pocket of the co-factor groove. Although these core pharmacophore-like molecules only exhibit low levels of inhibitory activity, these molecular snapshots provide a rational basis for renewed structure-based development of naphthalene-based compounds as anti-malarial agents.     

Erythrocyte surface glycosylphosphatidyl inositol anchored receptor for the malaria parasite

Parasitophorous vacuole formation is a critical step for the successful invasion of host erythrocytes by the malaria parasite. Rhoptry proteins are believed to have essential roles in vacuole formation, although their biological roles are poorly understood. To understand the molecular interactions between parasite rhoptry proteins and the erythrocyte during invasion, we have characterized the binding specificity of the high molecular mass rhoptry protein (RhopH) complex to erythrocytes using the rodent malaria parasite, Plasmodium yoelii. RhopH complex binding to erythrocytes was species-specific, observed with mouse but not rabbit or human erythrocytes. Binding is abolished following treatment of erythrocytes with trypsin or chymotrypsin. Because host cell cholesterol-rich membrane domains are recruited into the nascent parasitophorous vacuole, we evaluated a possible role of RhopH complex binding to the cholesterol-rich membrane domain-associated glycosylphosphatidyl inositol (GPI)-anchored protein. Using chimeric mice harboring GPI-deficient erythrocytes, RhopH complex binding to GPI-deficient mouse erythrocytes was undetectable, indicating involvement of GPI-anchored protein in PyRhopH complex binding. Furthermore, a significant reduction of P. yoelii parasite infection of GPI-deficient erythrocytes was observed in vivo, probably due to inefficient invasion. We conclude that the major erythrocyte receptor for PyRhopH complex is a protein attached to the erythrocyte surface via GPI-anchor and that GPI-deficient erythrocytes are resistant to P. yoelii invasion.     

Structural analogs of sialic acid interfere with the binding of erythrocyte binding antigen-175 to glycophorin A, an interaction crucial for erythrocyte invasion by Plasmodium falciparum

Plasmodium falciparum causes the most virulent form of malaria and remains a major worldwide health problem. The erythrocytic development of P. falciparum relies on parasite invasion of host erythrocytes, a process mediated in part by the interaction of erythrocyte binding antigen 175 (EBA-175) with the erythrocyte receptor glycophorin A (GA). The binding domain of EBA-175 that interacts with glycophorin A is a approximately 330 residues module called F2. Several studies have shown that F2 recognizes both sialic acids and the protein backbone on glycophorin A. Here, we have developed ELISA-based quantitative F2-GA binding assays. We also performed a series of competitive inhibition assays to block the F2-GA interaction using a variety of sialic acid analogs. Our data show that both 2,3-didehydro-2-deoxy-N-acetyl neuraminic acid (DANA) and 3'-N-acetyl neuraminyl-N-acetyl lactosamine are excellent inhibitors of the F2-GA interaction. Moderate levels of inhibition were also observed with monomers or oligomers of N-acetyl neuraminic acid (sialic acid). Furthermore, we show that DANA is able to significantly inhibit the invasion of erythrocytes by P. falciparum. Together, our ELISA-based binding assays and in vitro inhibition of erythrocyte invasion data suggest that small variations in the structures of DANA and related inhibitors can result in even more potent invasion inhibitory activities. Our studies provide a platform for the development of high potency inhibitors of the F2-GA interaction using high throughput drug discovery technologies. Such compounds may form part of inhibitor cocktails, which aim to block invasion of erythrocytes by P. falciparum.     

A member of a conserved Plasmodium protein family with membrane-attack complex/perforin (MACPF)-like domains localizes to the micronemes of sporozoites

Pore-forming proteins are employed by many pathogens to achieve successful host colonization. Intracellular pathogens use pore-forming proteins to invade host cells, survive within and productively interact with host cells, and finally egress from host cells to infect new ones. The malaria-causing parasites of the genus Plasmodium evolved a number of life cycle stages that enter and replicate in distinct cell types within the mosquito vector and vertebrate host. Despite the fact that interaction with host-cell membranes is a central theme in the Plasmodium life cycle, little is known about parasite proteins that mediate such interactions. We identified a family of five related genes in the genome of the rodent malaria parasite Plasmodium yoelii encoding secreted proteins all bearing a single membrane-attack complex/perforin (MACPF)-like domain. Each protein is highly conserved among Plasmodium species. Gene expression analysis in P. yoelii and the human malaria parasite Plasmodium falciparum indicated that the family is not expressed in the parasites blood stages. However, one of the genes was significantly expressed in P. yoelii sporozoites, the stage transmitted by mosquito bite. The protein localized to the micronemes of sporozoites, organelles of the secretory invasion apparatus intimately involved in host-cell infection. MACPF-like proteins may play important roles in parasite interactions with the mosquito vector and transmission to the vertebrate host.     

Trypanosoma cruzi antigen that interacts with the beta1-adrenergic receptor and modifies myocardial contractile activity

Previously, we have demonstrated that plasma membranes from the parasite Trypanosoma cruzi (T. cruzi) recognize and adhere to host cells through parasite surface attachment molecules that have affinity for beta(1)-adrenergic receptors (beta(1)-ARs) on target organs. In this report we identify a parasite protein that not only interacts with beta(1)-ARs, but also displays beta-agonist-like activity. We demonstrate that a recombinant maltose binding protein fusion of Tc13 Tul (MBP-Tc13 Tul), a member of the T. cruzi antigen 13 family of surface antigen proteins, competes for binding sites with the beta-adrenergic receptor antagonist [125I]-CYP on membranes purified both from CHO cells expressing human beta(1)-ARs and from rat atria. The competition is prevented by pre-treating MBP-Tc13 Tul with antibodies directed against the EPKSA repeat domain of Tc13 Tul, implicating this portion of the molecule in binding to the beta(1)-AR. Furthermore, MBP-Tc13 Tul activates rat myocardial beta(1)-ARs, resulting in synthesis of cyclic adenosine monophosphate (cAMP) and an increase in cardiac contractility. These biological effects are selectively suppressed by the beta(1)-AR antagonist atenolol, by a synthetic peptide corresponding to the second extracellular loop of the human beta(1)-AR, and by the anti-EPKSA repeat antibodies. These results imply that the Tc13 Tul cell-surface antigen of T. cruzi plays a central role in misregulating the beta(1)-AR following parasite infection, and may be a causative factor of dysautonomic syndrome described in Chagas' disease.     

Depletion of the Plasmodium berghei thrombospondin-related sporozoite protein reveals a role in host cell entry by sporozoites

The malaria parasite sporozoite stage develops in the mosquito vector and is transmitted to the mammalian host by bite. Sporozoites engage in multiple interactions with vector and host tissue on the journey from their oocyst origin to their final destination inside hepatocytes. Several malaria proteins have been identified that mediate sporozoite interactions with target tissues such as secreted and surface-associated ligands CSP and TRAP, which contain a thrombospondin type 1 repeat (TSR). Recently, we identified thrombospondin-related sporozoite protein (TRSP) in Plasmodium sporozoites, which exhibits a single TSR in its putative extracellular N-terminal region and is highly conserved among Plasmodium species. Here, we show using targeted gene disruption in the rodent malaria model Plasmodium berghei, that lack of TRSP has no effect on the asexual blood stage cycle, parasite transmission to the mosquito, sporozoite development and infection of mosquito salivary glands. However, analysis of TRSP knockout sporozoites in vitro and in vivo indicates that this protein has a significant role in hepatocyte entry and therefore liver infection. Thus, TRSP is an additional TSR-containing malaria parasite protein that is mainly involved in initial infection of the mammalian host.     

Multimerization of the Toxoplasma gondii MIC2 integrin-like A-domain is required for binding to heparin and human cells

Toxoplasma gondii is an obligate intracellular parasite that causes toxoplasmosis in humans and animals. To invade host cells, T. gondii deploys the contents of its apically oriented secretory organelles that include the micronemes. Contained within the micronemes are proteins that possess adhesive motifs resembling those found in mammalian proteins. The micronemal protein MIC2 is a member of the thrombospondin-related anonymous protein (TRAP) family of adhesive proteins, which characteristically feature at least one integrin-like A-domain. Because of its strict conservation within the family, we sought to define the role of this domain by testing the adhesive properties of recombinant MIC2 A-domain fusion proteins. Since MIC2 is found as a multimeric species in parasite lysate, we also wanted to test whether recombinant MIC2 A-domain bound to its substrate in a multimeric state. In vitro assays of binding to several different potential receptors revealed that the MIC2 A-domain binds specifically to heparin, a ubiquitous sulfated proteoglycan found in the extracellular matrix (ECM). Additional studies demonstrated that this binding is not dependent on the MIDAS site, a well-conserved divalent cation-binding motif that the MIC2 A-domain shares with its mammalian counterparts. The recombinant MIC2 A-domain bound to heparin as a high molecular weight species, as did MIC2 from parasite lysate, indicating that the recombinant A-domain mimics the binding of native MIC2. Multimerization of MIC2 may increase the number of interactions with host cell receptors, thereby forming a multivalent adhesive junction during parasite entry.     

The C-terminal domain of the Plasmodium falciparum acyl-CoA synthetases PfACS1 and PfACS3 functions as ligand for ankyrin

Infection of erythrocytes by the malaria parasite Plasmodium falciparum results in the export of several parasite proteins into the erythrocyte cytoplasm establishing novel interactions between host and parasite proteins, particularly at the membrane skeleton that modifies both the structural and functional properties of the red cell. We present evidences that two members of the P. falciparum acyl-CoA synthetase (PfACS) family, responsible for the activation of long-chain fatty acids by thio-esterification with CoA, are transported in vesicle-like structures toward the host erythrocyte cytoplasm where they interact with the cytoskeletal protein ankyrin. Carboxyl-terminal domain (CTD) overlay studies indicated that PfACS1 and PfACS3 bind to the 78-kDa fragment of ankyrin corresponding with its spectrin-binding domain. Co-immunoprecipitation of ankyrin and PfACS1/3 indicates that at least a fraction of these proteins are physically associated in the infected erythrocytes and provide evidence for a novel specific interaction which suggest that such a binding may bring these enzymes closer to the host erythrocyte membrane where exogenous fatty acids are available.     

Nonspecific immunoglobulin M binding and chondroitin sulfate A binding are linked phenotypes of Plasmodium falciparum isolates implicated in malaria during pregnancy

Binding of immunoglobulin M (IgM) antibodies from normal human serum to the surface of Plasmodium falciparum-infected red blood cells (iRBC) has previously been demonstrated only in parasites that form rosettes with uninfected red cells. We show that natural, nonspecific IgM but not IgG, IgA, IgD, or IgE also binds to the surface of iRBC selected for adhesion to chondroitin sulfate A (CSA), a placental receptor for parasites associated with malaria in pregnancy. The protease sensitivity of IgM-binding appears to match that of CSA binding, suggesting that the two phenotypes may be mediated by the same parasite molecule. We also show that a wide range of mouse monoclonal antibodies of the IgM class bind nonspecifically to CSA-selected iRBC, an important consideration in the interpretation of immunological assays performed on these parasite lines.     

Identification of Plasmodium falciparum var1CSA and var2CSA domains that bind IgM natural antibodies

Malaria in pregnancy is responsible for maternal anaemia, low-birth-weight babies and infant deaths. Plasmodium falciparum infected erythrocytes are thought to cause placental pathology by adhering to host receptors such as chondroitin sulphate A (CSA). CSA binding infected erythrocytes also bind IgM natural antibodies from normal human serum, a process that may facilitate placental adhesion or promote immune evasion. The parasite ligands that mediate placental adhesion are thought to be members of the variant erythrocyte surface antigen family P. falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by the var genes. Two var gene sub-families, var1CSA and var2CSA, have been identified as parasite CSA binding ligands and are leading candidates for a vaccine to prevent pregnancy-associated malaria. We investigated whether these two var gene subfamilies implicated in CSA binding are also the molecules responsible for IgM natural antibody binding. By heterologous expression of domains in COS-7 cells, we found that both var1CSA and var2CSA PfEMP1 variants bound IgM, and in both cases the binding region was a DBL epsilon domain occurring proximal to the membrane. None of the domains from a control non-IgM-binding parasite (R29) bound IgM when expressed in COS-7 cells. These results show that PfEMP1 is a parasite ligand for non-immune IgM and are the first demonstration of a specific adhesive function for PfEMP1 epsilon type domains.     

var genes, PfEMP1 and the human host

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is an important virulence factor encoded by a family of roughly 60 var genes and is used by the parasite to interact with the human host. The parasite regularly exchanges the expressed var gene generating antigenic variation of the infected RBCs (pRBC) surface which is crucial for successful proliferation and transmission. PfEMP1 is also an adhesive molecule that binds to an array of human receptors. By sequestration in the post-capillary venules, pRBCs are able to escape the spleen-mediated clearance but severe malaria may develop if the local binding is extensive. Anti-PfEMP1 immunity is important for preventing the development of both cerebral malaria and placental malaria, but more immunological studies on PfEMP1 antigens and their interaction with the human host are needed. Over the last few years our knowledge about var genes and PfEMP1s has increased dramatically through genetic, biochemical, immunological and epidemiological studies. In addition, the genome sequence has also provided us with a new platform for further dissecting its biological functions. This review highlights the recent analyses of var genes in the P. falciparum genome and postulates significance of genome recombination to the diversity of parasite virulence.     

Molecular basis of binding of the Plasmodium falciparum receptor BAEBL to erythrocyte receptor glycophorin C

Plasmodium falciparum invades human erythrocytes by redundant pathways. Unlike Plasmodium vivax that has one Duffy Binding-Like (DBL) receptor, P. falciparum has four members of the DBL receptor family. Furthermore, one of these DBL genes, BAEBL, has polymorphisms at four amino acids in region II; each polymorphism binds to a different erythrocyte receptor. One BAEBL variant (VSTK) binds specifically to erythrocyte glycophorin C and binds poorly to neuraminidase-treated erythrocytes. When the amino acid threonine (T121) in BAEBL (VSTK) is changed to a lysine (VSKK), it no longer requires sialic acid as a receptor. To explore the molecular basis of sialic acid binding, we modeled the structure of region II of BAEBL (VSTK) on the crystal structure of a related DBL receptor, region II of erythrocyte binding antigen-175 (EBA-175). Four charged amino acids, R52, R114, E54 and D125, are predicted to surround T121 in BAEBL (VSTK). They were individually mutated to alanine (R52A, R114A, E54A, and D125A) or lysine (R52K, R114K) and expressed on the surface of Chinese hamster ovary (CHO-K1) cells. BAEBL (VSTK) with mutations in R52 or R114 of BAEBL (VSTK) bound neuraminidase-treated erythrocytes. Unlike the arginine mutations, E54A and D125A still bound poorly to neuraminidase-treated erythrocytes. These findings suggest that the two arginine residues surrounding T121 are critical for the binding specificity of BAEBL (VSTK) to sialic acid and suggest a role for arginine in sialic acid binding independent of its negative charge.     

Host vascular endothelial growth factor is trophic for Plasmodium falciparum-infected red blood cells

Plasmodium falciparum, the protozoan parasite responsible for severe malaria infection, undergoes a complex life cycle. Infected red blood cells (iRBC) sequester in host cerebral microvessels, which underlies the pathology of cerebral malaria. Using immunohistochemistry on post mortem brain samples, we demonstrated positive staining for vascular endothelial growth factor (VEGF) on iRBC. Confocal microscopy of cultured iRBC revealed accumulation of VEGF within the parasitophorous vacuole, expression of host VEGF-receptor 1 and activated VEGF-receptor 2 on the surface of iRBC, but no accumulation of VEGF receptors within the iRBC. Addition of VEGF to parasite cultures had a trophic effect on parasite growth and also partially rescued growth of drug treated parasites. Both these effects were abrogated when parasites were grown in serum-free medium, suggesting a requirement for soluble VEGF receptor. We conclude that P. falciparum iRBC can bind host VEGF-R on the erythrocyte membrane and accumulate host VEGF within the parasitophorous vacuole, which may have a trophic effect on parasite growth.     

Naturally acquired and vaccine-elicited antibodies block erythrocyte cytoadherence of the Plasmodium vivax Duffy binding protein

Malaria merozoites require the presence of specific surface receptors on the red blood cell for invasion. Plasmodium vivax, requires the Duffy blood group antigen as an obligate receptor for invasion. The parasite Duffy binding protein (DBP) is the ligand involved in this process, making the DBP a potential vaccine candidate. A preliminary objective was to study whether people exposed to vivax malaria acquire antibodies that have the ability to block erythrocyte cytoadherence to the PvDBP. In comparison, we studied the immunogenicity of various recombinant DBP vaccines and investigated their potential to induct antifunctional antibodies. In order to do so, recombinant proteins to different regions of the putative ectodomain of the DBP and a DNA vaccine were used to immunize laboratory animals. An in vitro cytoadherence assay was used to investigate the presence of antifunctional antibodies in plasmas from people naturally exposed to vivax malaria, as well as in antisera obtained by animal vaccination. Our results showed that human plasma from populations naturally exposed to vivax malaria, as well as antisera obtained by vaccination using recombinant proteins, a DNA vaccine, and a synthetic peptide to DBP, inhibited in vitro binding of human erythrocytes to the DBP ligand domain (DBP(II)) in correlation to their previously measured antibody titer. Our results provide further evidence for the vaccine potential of this essential parasite adhesion molecule.     

Glycoprotein recognition mediates attachment of Plasmodium chabaudi to mouse erythrocytes

The interaction between Plasmodium falciparum merozoites and human erythrocytes is mediated by specific parasite proteins and sialoglycoproteins (SGPs) on the surface of the host cell. To investigate whether a similar mechanism functions in rodent malaria, a series of experiments was performed to identify the proteins involved in the interaction of Plasmodium chabaudi parasites and mouse erythrocytes. Labeled parasite proteins incubated with purified mouse SGP bound specifically to glycoprotein 2.1. Two parasite proteins (72 and 126 kilodaltons [kDa]) were coprecipitated with antibody directed to mouse erythrocyte membrane proteins. The lower band (72 kDa) as well as a band of 105 kDa were also observed to bind to N-acetyl-D-galactosamine affinity columns, suggesting a carbohydrate component in the binding of these parasites to erythrocytes. These experiments indicate that P. chabaudi possesses specific proteins which recognized SGP on the surface of murine erythrocytes in a manner similar to that of the merozoites of P. falciparum. Thus P. chabaudi in mice may provide an in vivo model of the human parasite for testing ways to inhibit merozoite recognition and invasion of host cells.     

Stage-specific variations in lectin binding to Leishmania donovani.

Visceral leishmaniasis is caused by the dimorphic protozoan Leishmania donovani, which exists as an aflagellar amastigote within mammalian mononuclear phagocytes and as a flagellated extracellular promastigote in its sandfly vector. We have identified four plant lectins that bind to the L. donovani surface, and through these we have documented stage-specific differences in exposed surface carbohydrates. Concanavalin A bound to both promastigotes and amastigotes; binding was inhibited by mannose or alpha-methyl-mannoside, implying a mannose-containing residue on the surface of both parasite stages. Ricinus communis agglutinin, which binds to galactose-containing residues, also bound to both stages and was inhibited by lactose, implying a galactose-containing glycoconjugate on the parasite surface. Two other lectins, wheat germ agglutinin (WGA) and peanut agglutinin (PNA), exhibited stage specificity in their binding characteristics. Amastigotes bound WGA but not PNA. During the process of conversion from the amastigote to the promastigote stage, the WGA-binding glycoconjugate was lost, and a PNA-binding residue was newly displayed. WGA binding was inhibited by N-acetyl-D-glucosamine and was not altered by neuraminidase treatment, suggesting the presence of an exposed N-acetyl-D-glucosamine moiety on the amastigote surface. The PNA binding site is known to accommodate the oligosaccharide beta-D-galactose-(1----3)-N-acetyl-D-galactosamine; in our system, PNA may have identified an internal rather than a terminal galactose on the promastigote surface. Localized binding of WGA and PNA to the surface of intermediate phases of the parasite suggested inhomogeneous and changing surface characteristics during conversion from amastigote to promastigote stages. This evolution of L. donovani surface glycoconjugates may be important in the adaptation of the organism to its divergent mammalian host and arthropod vector environments.     

The role of PfEMP1 adhesion domain classification in Plasmodium falciparum pathogenesis research

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family has a key role in parasite survival, transmission, and virulence. PfEMP1 are exported to the erythrocyte membrane and mediate binding of infected erythrocytes to the endothelial lining of blood vessels. This process aids parasite survival by avoiding spleen-dependent killing mechanisms, but it is associated with adhesion-based disease complications. Switching between PfEMP1 proteins enables parasites to evade host immunity and modifies parasite tropism for different microvascular beds. The PfEMP1 protein family is one of the most diverse adhesion modules in nature. This review covers PfEMP1 adhesion domain classification and the significant role it is playing in deciphering and deconvoluting P. falciparum cytoadhesion and disease.