proteins of the host rbc, such as spectrin, actin, ankyrin r, and spectrin–actin band 4.1 complex. upon arrival at the knob, pfemp1 is attached to the spectrin network using the phist proteins. function model of binding of rbc and wbc infected by p. falciparum to endothelial cells. the primary function of pfemp1 is to bind and attach rbcs to the wall of the blood vessels. the most important binding properties of p. falciparum known to date are mediated by the head structure of pfemp1, consisting of dbl domains and cidrs. dbl domains can bind to a variety of cell receptors including thrombospondin (tsp), complement receptor 1 (cr1), chondroitin sulfate a (csa), p-selectin, endothelial protein c receptor (epcr), and heparan sulfate. the dbl domain adjacent to the head structure binds to icam-1. cidrs mainly bind to a large variety of cluster determinant 36 (cd36). these bindings produce the pathogenic characteristics of the parasite, such as sequestration of infected cells in different tissues, invasion of rbcs, and clustering of infected cells by a process called rosetting. the rbc-binding site of pfemp1. (a) the head structure (mauve = nts region, grey = dbl1α1, orange = cidr1γ) with the docked blood group a (green-blue-black sticks) and heparin (yellow-black sticks) molecules. (b) detail of the rbc-binding site with bound molecules (yellow = c, blue =n, red = o). cidr1 protein in the semi-conserved head structure is the principal and best understood adhesion site of pfemp1. it binds with cd36 on endothelial cells. only group b and c proteins are able to bind, and that too with only those having cidrα2-6 sequence types. on the other hand, group a proteins have either cidrα1 or cidrβ/γ/δ, and they are responsible for the most severe condition of malaria. binding with icam-1 is achieved through the dblβ domain adjacent to the head structure. however, many pfemp1s having dblβ domain do not bind to icam-1, and it appears that only the dblβ paired with c2 domain can to bind to icam-1. the dblα-cidrγ tandem pair is the main factor for rosetting, sticking together the infected rbc with the uninfected cells, and thereby clogging of the blood vessels. this activity is performed through binding with cr1. the most dangerous malarial infection is in the brain and is called cerebral malaria. in cerebral malaria, the pfemp1 proteins involved are dc8 and dc13. they are named after the number of domain cassettes they contain, and are capable of binding not only endothelial cells of the brain, but also in different organs including brain, lung, heart, and bone marrow. initially, it was assumed that pfemp1 binds to icam-1 in the brain, but dc8 and dc13 were found incompatible with icam-1. instead dc8 and dc13 specifically bind to epcr using cidrα sub-types such as cidrα1.1, cidrα1.4, cidrα1.5 and cidrα1.7. however, it was later shown that dc13 can bind to both icam-1 and epcr. epcr is thus a potential vaccine and drug target in cerebral malaria. var2csa is unique in that it is mostly produced by the placenta during pregnancy (the condition called pregnancy-associated malaria, pam, or placental malaria). the majority of pam is therefore due to var2sca. unlike other pfemp1, var2csa binds to chondroitin sulfate a present on the vascular endothelium of the placenta. although its individual domains can bind to csa, its entire structure is used for complete binding. the major complication in pam is low-birth-weight babies. however, women who survived the first infection generally develop an effective immune response. in p. falciparum-prevalent regions in africa, pregnant women are found to contain high levels of antibody (immunoglobulin g, or igg) against var2csa, which protect them the placenta-attacking malarial parasite. they are noted for giving birth to heavier babies. clinical importance in a normal human immune system, malarial parasite binding to rbcs stimulates the production of antibodies that attack the pfemp1 molecules. binding of antibody with pfemp1 disables the binding properties of dbl domains, causing loss of cell adhesion, and the infected rbc is destroyed. in this scenario, malaria is avoided. however, to evade the host's immune response, different p. falciparum switch on and off different var genes to produce functionally different (antigenically distinct) pfemp1s. each variant type of pfemp1 has different binding property, and thus, is not always recognized by antibodies. by default, all the var genes in the malarial parasite are inactivated. activation (gene expression) of var is initiated upon infection of the organs. further, in each organ only specific var genes are activated. the severity of the infection is determined by the type of organ in which infection occurs, hence, the type of var gene activated. for examples, in the most severe cases of malaria, such as cerebral malaria, only the var genes for the pfemp1 proteins dc8 and dc13 are switched on. upon the synthesis of dc8 and dc13, their cidrα1 domains bind to epcr, which brings about the onset of severe malaria. the abundance of the gene products (transcripts) of these pfemp1 proteins (specifically the cidrα1 subtype transcripts) directly relates to the severity of the disease. this further indicates that preventing the interaction between cidrα1 and epcr would be good target for a potential vaccine. in pregnancy-associated malaria, another severe type of falciparum malaria, the gene for var2csa (named var2csa) is activated in the placenta. binding of var2csa to csa is the primary cause of premature delivery, death of the foetus and severe anaemia in the mother. this indicates that drugs targeting var2csa will be able to prevent the effects of malaria, and for this reason var2csa is the leading candidate for development of a pam vaccine.