View source for Plasmodium falciparum erythrocyte membrane protein 1

{{italic title|string=Plasmodium falciparum}}
{{Pfam box
|Name=PfEMP1, N-terminal segment
|InterPro=IPR029210
|Symbol=NTS
|Pfam=PF15447
}}
{{Pfam box
|Name=PfEMP DBL domain
|Pfam=PF03011
|Symbol=PFEMP
|InterPro=IPR004258
|CATH=2yk0A03
}}
{{Pfam box
|Name=PfEMP CIDR1γ
|Symbol=CIDR1_gamma
|Pfam=PF18562
|InterPro=IPR041480
}}
{{Pfam box
|Name=PfEMP1, acidic terminal segment
|Pfam=PF15445 
|InterPro=IPR029211
|Symbol=ATS
}}
'''''Plasmodium falciparum'' erythrocyte membrane protein 1''' ('''PfEMP1''') is a family of proteins present on the [[Cell membrane|membrane surface]] of [[red blood cell]]s (RBCs or erythrocytes) that are infected by the malarial parasite ''[[Plasmodium falciparum]]''. PfEMP1 is synthesized during the parasite's [[Apicomplexan life cycle|blood stage]] (erythrocytic [[Fission (biology)|schizogony]]) inside the RBC, during which the clinical symptoms of [[falciparum malaria]] are manifested. Acting as both an [[antigen]] and [[adhesion]] protein, it is thought to play a key role in the high level of virulence associated with ''P. falciparum''. It was discovered in 1984 when it was reported that infected RBCs had unusually large-sized cell membrane proteins, and these proteins had [[Antigen-antibody interaction|antibody-binding]] (antigenic) properties. An elusive protein, its chemical structure and molecular properties were revealed only after a decade, in 1995. It is now established that there is not one but a large family of PfEMP1 proteins, genetically regulated (encoded) by a group of about 60 genes called ''var''. Each ''P. falciparum'' is able to switch on and off specific ''var'' genes to produce a  [[Antigenic variation|functionally different protein]], thereby evading the host's immune system. RBCs carrying PfEMP1 on their surface stick to [[Endothelium|endothelial cells]], which facilitates further binding with uninfected RBCs (through the processes of sequestration and rosetting), ultimately helping the parasite to both spread to other RBCs as well as bringing about the fatal symptoms of ''P. falciparum'' malaria.

==Introduction==
[[File:Erythrocyte knobs.png|thumb|right| Images of RBCs infected by ''P. falciparum'' using atomic force microscopy. (A) An early schizont with cluster of knobs at the center. Scale bar = 1 μm. Inset is the same image under light microscope. (B) A young trophozoite with knobs. Scale bar = 1 μm. (C) A close up of the cell membrane showing individual knobs. Scale bar = 200 nm. (D) A close up of a single knob. Scale bar = 75 nm.<ref name=quadt/>]]
Malaria is the deadliest among infectious diseases, accounting for approximately 429,000 human deaths in 2015 as of the latest estimate by the [[World Health Organization]].<ref name="WHO">{{cite web|title=Malaria Fact sheet|url=https://www.who.int/mediacentre/factsheets/fs094/en/|publisher=WHO Media Centre|access-date=5 November 2016|date=April 2016}}</ref> In humans, malaria can be caused by five ''Plasmodium'' parasites, namely ''P. falciparum'', ''P. vivax'', ''P. malariae'', ''P. ovale'' and ''P. knowlesi''.<ref>{{cite journal | vauthors = Cox FE | title = History of the discovery of the malaria parasites and their vectors | journal = Parasites & Vectors | volume = 3 | issue = 1 | pages = 5 | date = February 2010 | pmid = 20205846 | pmc = 2825508 | doi = 10.1186/1756-3305-3-5 | doi-access = free }}</ref> ''P. falciparum'' is the most dangerous species, attributed to >99% of malaria's death toll, with 70% of these deaths occurring in children under the age of five years.<ref name="WHO"/> The parasites are transmitted through the bites of female mosquitos (of the species of ''Anopheles''). Before invading the RBCs and causing the symptoms of malaria, the parasites first multiply in the liver. The daughter parasites called [[merozoites]] then only infect the RBCs. They undergo structural development inside the RBCs, becoming [[trophozoites]] and schizonts. It is during this period that malarial symptoms are produced.<ref>{{cite journal | vauthors = Antinori S, Galimberti L, Milazzo L, Corbellino M | title = Biology of human malaria plasmodia including Plasmodium knowlesi | journal = Mediterranean Journal of Hematology and Infectious Diseases | volume = 4 | issue = 1 | pages = e2012013 | date = 2012 | pmid = 22550559 | pmc = 3340990 | doi = 10.4084/MJHID.2012.013 }}</ref>

Unlike RBCs infected by other ''Plasmodium'' species, ''P. falciparum''-infected RBCs had been known to spontaneously stick together. By the early 1980s, it was established that when the parasite (both the trophozoite and schizont forms) enters the blood stream and infects RBCs, the infected cells form knobs on their surface. Then they become sticky, and get attached to the walls (endothelium) of the blood vessels through a process called cytoadhesion, or cytoadherence.<ref name=rowe09>{{cite journal | vauthors = Rowe JA, Claessens A, Corrigan RA, Arman M | title = Adhesion of Plasmodium falciparum-infected erythrocytes to human cells: molecular mechanisms and therapeutic implications | journal = Expert Reviews in Molecular Medicine | volume = 11 | pages = e16 | date = May 2009 | pmid = 19467172 | pmc = 2878476 | doi = 10.1017/S1462399409001082 }}</ref> Such attachment favours binding with and accumulation of other RBCs. This process is known as sequestration.<ref>{{cite journal | vauthors = Sharma YD | title = Knobs, knob proteins and cytoadherence in falciparum malaria | journal = The International Journal of Biochemistry | volume = 23 | issue = 9 | pages = 775–89 | date = 1991 | pmid = 1773882 | doi = 10.1016/0020-711X(91)90061-Q }}</ref> It is during this condition that the parasites induce an immune response (antigen-antibody reaction) and evade destruction in the spleen.<ref>{{cite journal | vauthors = David PH, Hommel M, Miller LH, Udeinya IJ, Oligino LD | title = Parasite sequestration in Plasmodium falciparum malaria: spleen and antibody modulation of cytoadherence of infected erythrocytes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 80 | issue = 16 | pages = 5075–9 | date = August 1983 | pmid = 6348780 | pmc = 384191 | doi = 10.1073/pnas.80.16.5075 | bibcode = 1983PNAS...80.5075D | doi-access = free }}</ref><ref>{{cite journal | vauthors = Berendt AR, Ferguson DJ, Newbold CI | title = Sequestration in Plasmodium falciparum malaria: sticky cells and sticky problems | journal = Parasitology Today | volume = 6 | issue = 8 | pages = 247–54 | date = August 1990 | pmid = 15463355 | doi = 10.1016/0169-4758(90)90184-6 }}</ref> Although the process and significance of sequestration were described in detail by two Italian physicians [[Amico Bignami]] and [[Ettore Marchiafava]] in the early 1890s, it took a century to discover the actual factor for the stickiness and virulence.<ref name=bull>{{cite journal | vauthors = Bull PC, Abdi AI | title = The role of PfEMP1 as targets of naturally acquired immunity to childhood malaria: prospects for a vaccine | journal = Parasitology | volume = 143 | issue = 2 | pages = 171–86 | date = February 2016 | pmid = 26741401 | pmc = 4825093 | doi = 10.1017/S0031182015001274 }}</ref><ref name="sherman08">{{cite book|last1=Sherman|first1=Irwin|title=Advances in Parasitology: Reflections on a Century of Malaria Biochemistry|date=2008|publisher=Academic Press|location=London (UK)|isbn=978-0-08-092183-9|pages=188–189|url=https://books.google.com/books?id=t9e81NrD0FIC}}</ref>

==Discovery==
PfEMP1 was discovered by [[Russell J. Howard]] and his colleagues at the US National Institutes of Health in 1984. Using the techniques of [[Iodination|radioiodination]] and [[immunoprecipitation]], they found a unique but yet unknown antigen from ''P. falciparum''-infected RBCs that appeared to cause binding with other cells.<ref>{{cite journal | vauthors = Pasloske BL, Howard RJ | title = Malaria, the red cell, and the endothelium | journal = Annual Review of Medicine | volume = 45 | issue = 1 | pages = 283–95 | date = 1994 | pmid = 8198384 | doi = 10.1146/annurev.med.45.1.283 }}</ref> Since the antigenic protein could only be detected in infected cells, they asserted that the protein was produced by the malarial parasite, and not by RBCs. The antigen was large and appeared to be different in size in different strains of ''P. falciparum'' obtained from [[night monkey]] (''Aotus''). In one strain, called Camp (from Malaysia), the antigen was found to have a molecular size of approximately 285 kDa; while in the other, called St. Lucia (from El Salvador), it was approximately 260 kDa. Both antigens bind to cultured skin cancer ([[melanoma]]) cells. But the researchers failed to confirm whether or not the protein actually was an adhesion molecule to the wall of blood vessels.<ref>{{cite journal | vauthors = Leech JH, Barnwell JW, Miller LH, Howard RJ | title = Identification of a strain-specific malarial antigen exposed on the surface of Plasmodium falciparum-infected erythrocytes | journal = The Journal of Experimental Medicine | volume = 159 | issue = 6 | pages = 1567–75 | date = June 1984 | pmid = 6374009 | pmc = 2187322 | doi = 10.1084/jem.159.6.1567 }}</ref> Later in the same year, they found out that the unknown antigen was associated only with RBCs having small lumps called knobs on their surface.<ref>{{cite journal | vauthors = Aley SB, Sherwood JA, Howard RJ | title = Knob-positive and knob-negative Plasmodium falciparum differ in expression of a strain-specific malarial antigen on the surface of infected erythrocytes | journal = The Journal of Experimental Medicine | volume = 160 | issue = 5 | pages = 1585–90 | date = November 1984 | pmid = 6208311 | pmc = 2187501 | doi = 10.1084/jem.160.5.1585 }}</ref> The first human RBC antigen was reported in 1986. Howard's team found that the antigens from Gambian children, who were suffering from falciparum malaria, were similar to those from the RBCs of night monkey. They determined that the molecular sizes of the proteins ranged from 250 to 300 kDa.<ref>{{cite journal | vauthors = Aley SB, Sherwood JA, Marsh K, Eidelman O, Howard RJ | title = Identification of isolate-specific proteins on sorbitol-enriched Plasmodium falciparum infected erythrocytes from Gambian patients | journal = Parasitology | volume = 92 ( Pt 3) | issue = 3 | pages = 511–25 | date = June 1986 | pmid = 3526259 | doi = 10.1017/S0031182000065410 | s2cid = 12585437 }}</ref>

In 1987, they discovered another type of surface antigen from the same Camp and St. Lucia strains of malarial parasites. This was also a large-sized protein of about 300 kDa, but quite different from the antigens reported in 1984. The new protein was unable to bind to melanoma cells and present only inside the cell. Hence, they named the earlier protein ''Plasmodium falciparum'' erythrocyte membrane protein 1 (PfEMP1), to distinguish it from the newly identified ''Plasmodium falciparum'' erythrocyte membrane protein 2 (PfEMP2).<ref>{{cite journal | vauthors = Howard RJ, Lyon JA, Uni S, Saul AJ, Aley SB, Klotz F, Panton LJ, Sherwood JA, Marsh K, Aikawa M | title = Transport of an Mr approximately 300,000 Plasmodium falciparum protein (Pf EMP 2) from the intraerythrocytic asexual parasite to the cytoplasmic face of the host cell membrane | journal = The Journal of Cell Biology | volume = 104 | issue = 5 | pages = 1269–80 | date = May 1987 | pmid = 2437128 | pmc = 2114467 | doi = 10.1083/jcb.104.5.1269 }}</ref> The distinction was confirmed the next year, with an additional information that PfEMP1 is relatively less in number.<ref>{{cite journal | vauthors = Howard RJ, Barnwell JW, Rock EP, Neequaye J, Ofori-Adjei D, Maloy WL, Lyon JA, Saul A | title = Two approximately 300 kilodalton Plasmodium falciparum proteins at the surface membrane of infected erythrocytes | journal = Molecular and Biochemical Parasitology | volume = 27 | issue = 2–3 | pages = 207–23 | date = January 1988 | pmid = 3278227 | doi = 10.1016/0166-6851(88)90040-0 }}</ref>

Although some of the properties of PfEMP1 were firmly established, the protein was difficult to isolate due to its low occurrence. Five years after its discovery, one of the original researchers Irwin Sherman began to doubt the existence of PfEMP1 as a unique protein.<ref name="sherman08"/> He argued that the antigen could be merely a surface protein of RBCs that changes upon infection with malarial parasites.<ref>{{cite journal | vauthors = Sherman IW, Winograd E | title = Antigens on the Plasmodium falciparum infected erythrocyte surface are not parasite derived | journal = Parasitology Today | volume = 6 | issue = 10 | pages = 317–20 | date = October 1990 | pmid = 15463255 | doi = 10.1016/0169-4758(90)90174-3 }}</ref> A consensus was achieved in 1995 following the identification (by [[cloning]]) of the gene for PfEMP1. The discovery of the genes was independently reported by Howard's team and two other teams at NIH. Howard's team identified two genes for PfEMP1, and [[Protein production|recombinant protein products]] of these genes were shown to have antigenic and adhesive properties. They further affirmed that PfEMP1 is the key molecule in the ability of ''P. falciparum'' to evade the host's immune system.<ref>{{cite journal | vauthors = Baruch DI, Pasloske BL, Singh HB, Bi X, Ma XC, Feldman M, Taraschi TF, Howard RJ | title = Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes | journal = Cell | volume = 82 | issue = 1 | pages = 77–87 | date = July 1995 | pmid = 7541722 | doi = 10.1016/0092-8674(95)90054-3 | s2cid = 700863 | doi-access = free }}</ref> Joseph D. Smith and others showed that PfEMP1 is actually a large family of proteins encoded by a multigene family called ''var''. The gene products can bind to a variety of receptors including those on endothelial cells.<ref>{{cite journal | vauthors = Smith JD, Chitnis CE, Craig AG, Roberts DJ, Hudson-Taylor DE, Peterson DS, Pinches R, Newbold CI, Miller LH | title = Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes | journal = Cell | volume = 82 | issue = 1 | pages = 101–10 | date = July 1995 | pmid = 7606775 | pmc = 3730239 | doi = 10.1016/0092-8674(95)90056-X }}</ref> Xin-Zhuan Su and others showed that there could be more than 50 ''var'' genes which are distributed on different chromosomes of the malarial parasite.<ref>{{cite journal | vauthors = Su XZ, Heatwole VM, Wertheimer SP, Guinet F, Herrfeldt JA, Peterson DS, Ravetch JA, Wellems TE | title = The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes | journal = Cell | volume = 82 | issue = 1 | pages = 89–100 | date = July 1995 | pmid = 7606788 | doi = 10.1016/0092-8674(95)90055-1 | s2cid = 18399506 | doi-access = free }}</ref>

== Structure ==
[[File:PfEMP1 diagrammatic structure.jpg|thumb|right|Typical structure of PfEMP1. NTS = N terminal segment. TMD = transmembrane domain. ATS = intracellular acidic terminal segment.]]
PfEMP1 is a large family of proteins having high molecular weights ranging from 200 to 350 kDa.<ref name=pasternak>{{cite journal | vauthors = Pasternak ND, Dzikowski R | title = PfEMP1: an antigen that plays a key role in the pathogenicity and immune evasion of the malaria parasite Plasmodium falciparum | journal = The International Journal of Biochemistry & Cell Biology | volume = 41 | issue = 7 | pages = 1463–6 | date = July 2009 | pmid = 19150410 | doi = 10.1016/j.biocel.2008.12.012 }}</ref> The wide range of molecular size reflects extreme variation in the amino acid composition of the proteins. But all the PfEMP1 proteins can be described as having three basic structural components, namely, an extracellular domain (ECD), a transmembrane domain (TMD) and an intracellular acidic terminal segment (ATS). The extracellular domain is fully exposed on the cell surface, and is the most variable region. It consists of a number of sub-domains, including a short and conserved N terminal segment (NTS) at the outermost region, followed by a highly variable [[Duffy antigen system|Duffy]]-binding-like (DBL) domain, sometimes a Ca<sup>2+</sup>-binding C2 domain, and then one or two cysteine-rich interdomain regions (CIDRs).<ref name=bull/><ref name=flick>{{cite journal | vauthors = Flick K, Chen Q | title = var genes, PfEMP1 and the human host | journal = Molecular and Biochemical Parasitology | volume = 134 | issue = 1 | pages = 3–9 | date = March 2004 | pmid = 14747137 | doi = 10.1016/j.molbiopara.2003.09.010 }}</ref>

Duffy-binding-like domains are so named because of their similarity to the [[Duffy binding proteins]] of ''[[Plasmodium vivax|P. vivax]]'' and ''[[Plasmodium knowlesi|P. knowlesi]]''.<ref>{{cite journal | vauthors = Chitnis CE, Miller LH | title = Identification of the erythrocyte binding domains of Plasmodium vivax and Plasmodium knowlesi proteins involved in erythrocyte invasion | journal = The Journal of Experimental Medicine | volume = 180 | issue = 2 | pages = 497–506 | date = August 1994 | pmid = 8046329 | pmc = 2191600 | doi = 10.1084/jem.180.2.497 }}</ref> There are six variant types of DBL, named DBLα, DBLβ, DBLγ, DBLδ, DBLε and DBLζ. CIDR is also divided into three classes: CIDRα, CIDRβ and CIDRγ.<ref>{{cite journal | vauthors = Smith JD, Subramanian G, Gamain B, Baruch DI, Miller LH | title = Classification of adhesive domains in the Plasmodium falciparum erythrocyte membrane protein 1 family | journal = Molecular and Biochemical Parasitology | volume = 110 | issue = 2 | pages = 293–310 | date = October 2000 | pmid = 11071284 | doi = 10.1016/S0166-6851(00)00279-6 }}</ref> Both DBL and CIDR have an additional type called PAM, so named because of their specific involvement in [[pregnancy-associated malaria]] (PAM).<ref>{{cite journal | vauthors = Dahlbäck M, Jørgensen LM, Nielsen MA, Clausen TM, Ditlev SB, Resende M, Pinto VV, Arnot DE, Theander TG, Salanti A | title = The chondroitin sulfate A-binding site of the VAR2CSA protein involves multiple N-terminal domains | journal = The Journal of Biological Chemistry | volume = 286 | issue = 18 | pages = 15908–17 | date = May 2011 | pmid = 21398524 | pmc = 3091200 | doi = 10.1074/jbc.M110.191510 | doi-access = free }}</ref> In spite of the diverse DBL and CIDR proteins, the extracellular amino terminal region is partly conserved, consisting of about 60 amino acids of NTS, one each of DBLα and CIDR1 proteins in tandem. This semi-conserved DBLα-CIDR1 region is called the head structure.<ref name=melcher/> The last CIDR region joins the TMD, which is embedded in the cell membrane. The TMD and ATS are highly conserved among different PfEMP1s,<ref name="hviid">{{cite book|last1=Hviid|first1=Lars|title=PfEMP1 – A Parasite Protein Family of Key Importance in Plasmodium falciparum Malaria Immunity and Pathogenesis|last2=Jensen|first2=Anja T.R.|editor1-last=Rollinson|editor1-first=D.|editor2-last=Stothard|editor2-first=J.R.|volume=88|date=2015|publisher=Elsevier|isbn=978-0-12-802268-9|pages=51–84|doi=10.1016/bs.apar.2015.02.004|pmid=25911365|chapter=PfEMP1 – A Parasite Protein Family of Key Importance in ''Plasmodium falciparum'' Malaria Immunity and Pathogenesis|series=Advances in Parasitology}}</ref> and their structures have been solved using [[Nuclear magnetic resonance spectroscopy of proteins|solution NMR]] ({{PDB|2LKL}}).<ref name="ReferenceA">{{cite journal | vauthors = Mayer C, Slater L, Erat MC, Konrat R, Vakonakis I | title = Structural analysis of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) intracellular domain reveals a conserved interaction epitope | journal = The Journal of Biological Chemistry | volume = 287 | issue = 10 | pages = 7182–9 | date = March 2012 | pmid = 22249178 | pmc = 3293552 | doi = 10.1074/jbc.M111.330779 | doi-access = free }}</ref>

The head structure is followed by a variable combination of diverse DBL and CIDR proteins, and in many cases along with C2. This variation gives rise to different types of PfEMP1. The DBL-CIDR combination in a particular type of PfEMP1 protein is never random, but organized into specific sequences known as domain cassettes.<ref>{{cite journal | vauthors = Trimnell AR, Kraemer SM, Mukherjee S, Phippard DJ, Janes JH, Flamoe E, Su XZ, Awadalla P, Smith JD | title = Global genetic diversity and evolution of var genes associated with placental and severe childhood malaria | journal = Molecular and Biochemical Parasitology | volume = 148 | issue = 2 | pages = 169–80 | date = August 2006 | pmid = 16697476 | doi = 10.1016/j.molbiopara.2006.03.012 }}</ref> In some domain cassettes, there are only two or few DBL domains and CIDR domains, but in others they cover the entire length of the PfEMP1. These differences are responsible for different binding capacity among different PfEMP1s.<ref name=rask>{{cite journal | vauthors = Lavstsen T, Turner L, Saguti F, Magistrado P, Rask TS, Jespersen JS, Wang CW, Berger SS, Baraka V, Marquard AM, Seguin-Orlando A, Willerslev E, Gilbert MT, Lusingu J, Theander TG | title = Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 26 | pages = E1791-800 | date = June 2012 | pmid = 22619319 | pmc = 3387094 | doi = 10.1073/pnas.1120455109 | doi-access = free }}</ref> For instance, among the most well-known types, VAR3 (earlier called type 3 PfEMP1) is the smallest, consisting of only NTS with DBL1α and DBL2ε domains in the ECD. Its molecular size is approximately 150 kDa.<ref>{{cite journal | vauthors = Zhang Y, Jiang N, Chang Z, Wang H, Lu H, Wahlgren M, Chen Q | title = The var3 genes of Plasmodium falciparum 3D7 strain are differentially expressed in infected erythrocytes | journal = Parasite | volume = 21 | pages = 19 | date = 2014 | pmid = 24759654 | pmc = 3996964 | doi = 10.1051/parasite/2014019 }}</ref> In domain cassette (DC) 4 type, the ECD is made up of three domains DBLα<sub>1.1/1.4</sub>, CIDRα<sub>1.6</sub> and DBLβ<sub>3</sub>. The DBLβ<sub>3</sub> domain contains a binding site for intercellular adhesion molecule 1 ([[ICAM-1|ICAM1]]). This is particularly implicated with the development of brain infection.<ref>{{cite journal | vauthors = Bengtsson A, Joergensen L, Rask TS, Olsen RW, Andersen MA, Turner L, Theander TG, Hviid L, Higgins MK, Craig A, Brown A, Jensen AT | title = A novel domain cassette identifies Plasmodium falciparum PfEMP1 proteins binding ICAM-1 and is a target of cross-reactive, adhesion-inhibitory antibodies | journal = Journal of Immunology | volume = 190 | issue = 1 | pages = 240–9 | date = January 2013 | pmid = 23209327 | pmc = 3539686 | doi = 10.4049/jimmunol.1202578 }}</ref> VAR2CSA is atypical in having a single domain cassette that consists of three N terminal DBL<sub>PAM</sub> domains followed by three DBLε domains and one CIDR<sub>PAM</sub>. The seven domains always occur together. The usual NTS is absent.<ref name="ReferenceB">{{cite journal | vauthors = Salanti A, Dahlbäck M, Turner L, Nielsen MA, Barfod L, Magistrado P, Jensen AT, Lavstsen T, Ofori MF, Marsh K, Hviid L, Theander TG | title = Evidence for the involvement of VAR2CSA in pregnancy-associated malaria | journal = The Journal of Experimental Medicine | volume = 200 | issue = 9 | pages = 1197–203 | date = November 2004 | pmid = 15520249 | pmc = 2211857 | doi = 10.1084/jem.20041579 }}</ref><ref>{{cite journal | vauthors = Hviid L, Salanti A | title = VAR2CSA and protective immunity against pregnancy-associated Plasmodium falciparum malaria | journal = Parasitology | volume = 134 | issue = Pt 13 | pages = 1871–6 | date = 2007 | pmid = 17958922 | doi = 10.1017/S0031182007000121 | s2cid = 7706073 | url = https://zenodo.org/record/999281 }}</ref> The protein specifically binds to chondroitin sulphate A (CSA); hence the name VAR2CSA.<ref>{{cite journal | vauthors = Salanti A, Staalsoe T, Lavstsen T, Jensen AT, Sowa MP, Arnot DE, Hviid L, Theander TG | title = Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria | journal = Molecular Microbiology | volume = 49 | issue = 1 | pages = 179–91 | date = July 2003 | pmid = 12823820 | doi = 10.1046/j.1365-2958.2003.03570.x | s2cid = 38384882 | doi-access = free }}</ref>

==Synthesis and transport==
[[File:PfEMP1 on knob.png|thumb|right| Model of a knob structure of ''P. falciparum''-infected RBC showing attachment of PfEMP1.<ref name=helms/>]]
The PfEMP1 proteins are regulated and produced (encoded) by about 60 different ''var'' genes,<ref>{{cite journal | vauthors = Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S, Paulsen IT, James K, Eisen JA, Rutherford K, Salzberg SL, Craig A, Kyes S, Chan MS, Nene V, Shallom SJ, Suh B, Peterson J, Angiuoli S, Pertea M, Allen J, Selengut J, Haft D, Mather MW, Vaidya AB, Martin DM, Fairlamb AH, Fraunholz MJ, Roos DS, Ralph SA, McFadden GI, Cummings LM, Subramanian GM, Mungall C, Venter JC, Carucci DJ, Hoffman SL, Newbold C, Davis RW, Fraser CM, Barrell B | title = Genome sequence of the human malaria parasite Plasmodium falciparum | journal = Nature | volume = 419 | issue = 6906 | pages = 498–511 | date = October 2002 | pmid = 12368864 | pmc = 3836256 | doi = 10.1038/nature01097 | bibcode = 2002Natur.419..498G }}</ref> but an individual ''P. falciparum'' would switch on only a single ''var'' gene at a time to produce only one type of PfEMP.<ref>{{cite journal | vauthors = Chen Q, Fernandez V, Sundström A, Schlichtherle M, Datta S, Hagblom P, Wahlgren M | title = Developmental selection of var gene expression in Plasmodium falciparum | journal = Nature | volume = 394 | issue = 6691 | pages = 392–5 | date = July 1998 | pmid = 9690477 | doi = 10.1038/28660 | bibcode = 1998Natur.394..392C | s2cid = 4408193 }}</ref><ref>{{cite journal | vauthors = Scherf A, Lopez-Rubio JJ, Riviere L | title = Antigenic variation in Plasmodium falciparum | journal = Annual Review of Microbiology | volume = 62 | issue = 1 | pages = 445–70 | date = 2008 | pmid = 18785843 | doi = 10.1146/annurev.micro.61.080706.093134 }}</ref> The ''var'' genes are distributed in two [[exon]]s. Exon 1 encodes amino acids of the highly variable ECD,<ref>{{cite journal | vauthors = Kyes SA, Kraemer SM, Smith JD | title = Antigenic variation in Plasmodium falciparum: gene organization and regulation of the var multigene family | journal = Eukaryotic Cell | volume = 6 | issue = 9 | pages = 1511–20 | date = September 2007 | pmid = 17644655 | pmc = 2043368 | doi = 10.1128/EC.00173-07 }}</ref> while exon 2 encodes those of the conserved TMD and ATS.<ref>{{cite journal | vauthors = Kyes SA, Christodoulou Z, Raza A, Horrocks P, Pinches R, Rowe JA, Newbold CI | title = A well-conserved Plasmodium falciparum var gene shows an unusual stage-specific transcript pattern | journal = Molecular Microbiology | volume = 48 | issue = 5 | pages = 1339–48 | date = June 2003 | pmid = 12787360 | pmc = 2869446 | doi = 10.1046/j.1365-2958.2003.03505.x }}</ref> Based on their location in the chromosome and sequence, the ''var'' genes are generally classified into three major groups, A, B, and C, and two intermediate groups, B/A and B/C;<ref name=bull/><ref>{{cite journal | vauthors = Kyriacou HM, Stone GN, Challis RJ, Raza A, Lyke KE, Thera MA, Koné AK, Doumbo OK, Plowe CV, Rowe JA | title = Differential var gene transcription in Plasmodium falciparum isolates from patients with cerebral malaria compared to hyperparasitaemia | journal = Molecular and Biochemical Parasitology | volume = 150 | issue = 2 | pages = 211–8 | date = December 2006 | pmid = 16996149 | pmc = 2176080 | doi = 10.1016/j.molbiopara.2006.08.005 }}</ref> or sometimes simply into five classes, ''upsA'', ''upsB'', ''upsC'', ''upsD'', and ''upsE'' respectively.<ref>{{cite journal | vauthors = Kirchner S, Power BJ, Waters AP | title = Recent advances in malaria genomics and epigenomics | journal = Genome Medicine | volume = 8 | issue = 1 | pages = 92 | date = September 2016 | pmid = 27605022 | pmc = 5015228 | doi = 10.1186/s13073-016-0343-7 | doi-access = free }}</ref> Groups A and B are found towards the terminal end ([[Subtelomere|subtelomeric]]) region of the chromosome, while group C is in the central ([[Centromere|centromeric]]) region.<ref>{{cite journal | vauthors = Rask TS, Hansen DA, Theander TG, Gorm Pedersen A, Lavstsen T | title = Plasmodium falciparum erythrocyte membrane protein 1 diversity in seven genomes--divide and conquer | journal = PLOS Computational Biology | volume = 6 | issue = 9 | pages = e1000933 | date = September 2010 | pmid = 20862303 | pmc = 2940729 | doi = 10.1371/journal.pcbi.1000933 | bibcode = 2010PLSCB...6E0933R | doi-access = free }}</ref><ref name=smith14>{{cite journal | vauthors = Smith JD | title = The role of PfEMP1 adhesion domain classification in Plasmodium falciparum pathogenesis research | journal = Molecular and Biochemical Parasitology | volume = 195 | issue = 2 | pages = 82–7 | date = July 2014 | pmid = 25064606 | pmc = 4159067 | doi = 10.1016/j.molbiopara.2014.07.006 }}</ref>

Once the PfEMP1 protein is fully synthesized ([[w:Translation (biology)|translated]]), it is carried to the cytoplasm towards the RBC membrane. The NTS is crucial for such directional movement.<ref name=melcher>{{cite journal | vauthors = Melcher M, Muhle RA, Henrich PP, Kraemer SM, Avril M, Vigan-Womas I, Mercereau-Puijalon O, Smith JD, Fidock DA |author9-link=David A. Fidock| title = Identification of a role for the PfEMP1 semi-conserved head structure in protein trafficking to the surface of Plasmodium falciparum infected red blood cells | journal = Cellular Microbiology | volume = 12 | issue = 10 | pages = 1446–62 | date = October 2010 | pmid = 20438573 | pmc = 2939972 | doi = 10.1111/j.1462-5822.2010.01481.x }}</ref> Within the cytoplasm, the newly synthesized protein is attached to a Golgi-like membranous vesicle called the [[Maurer's cleft]].<ref>{{cite journal | vauthors = Mundwiler-Pachlatko E, Beck HP | title = Maurer's clefts, the enigma of Plasmodium falciparum | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 50 | pages = 19987–94 | date = December 2013 | pmid = 24284172 | pmc = 3864307 | doi = 10.1073/pnas.1309247110 | bibcode = 2013PNAS..11019987M | doi-access = free }}</ref> Inside the Maurer's clefts is a family of proteins called ''Plasmodium'' helical interspersed subtelomeric ([[PHIST]]) proteins. Of the PHIST proteins, PFI1780w and PFE1605w bind the intracellular ATS of PfEMP1 during transport to the RBC membrane.<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Warncke JD, Vakonakis I, Beck HP | title = Plasmodium Helical Interspersed Subtelomeric (PHIST) Proteins, at the Center of Host Cell Remodeling | journal = Microbiology and Molecular Biology Reviews | volume = 80 | issue = 4 | pages = 905–27 | date = December 2016 | pmid = 27582258 | pmc = 5116875 | doi = 10.1128/MMBR.00014-16 | url = https://zenodo.org/record/1000776 }}</ref>

The PfEMP1 molecule is deposited at the RBC membrane at the knobs.<ref>{{cite journal | vauthors = Cooke B, Coppel R, Wahlgren M | title = Falciparum malaria: sticking up, standing out and out-standing | journal = Parasitology Today | volume = 16 | issue = 10 | pages = 416–20 | date = October 2000 | pmid = 11006472 | doi = 10.1016/S0169-4758(00)01753-1 }}</ref> These knobs are easily identified as conspicuous bumps on the infected RBCs from the early trophozoite stage onward.<ref>{{cite journal | vauthors = Nagao E, Kaneko O, Dvorak JA | title = Plasmodium falciparum-infected erythrocytes: qualitative and quantitative analyses of parasite-induced knobs by atomic force microscopy | journal = Journal of Structural Biology | volume = 130 | issue = 1 | pages = 34–44 | date = May 2000 | pmid = 10806089 | doi = 10.1006/jsbi.2000.4236 | url = https://zenodo.org/record/1229912 }}</ref> The malarial parasite cannot induce its virulence on RBCs without knobs.<ref>{{cite journal | vauthors = Maier AG, Rug M, O'Neill MT, Brown M, Chakravorty S, Szestak T, Chesson J, Wu Y, Hughes K, Coppel RL, Newbold C, Beeson JG, Craig A, Crabb BS, Cowman AF | title = Exported proteins required for virulence and rigidity of Plasmodium falciparum-infected human erythrocytes | journal = Cell | volume = 134 | issue = 1 | pages = 48–61 | date = July 2008 | pmid = 18614010 | pmc = 2568870 | doi = 10.1016/j.cell.2008.04.051 }}</ref> As many as 10,000 knobs are distributed throughout the surface of a mature infected RBC, and each knob is 50-80&nbsp;nm in diameter.<ref name=quadt>{{cite journal | vauthors = Quadt KA, Barfod L, Andersen D, Bruun J, Gyan B, Hassenkam T, Ofori MF, Hviid L | title = The density of knobs on Plasmodium falciparum-infected erythrocytes depends on developmental age and varies among isolates | journal = PLOS ONE | volume = 7 | issue = 9 | pages = e45658 | date = 2012 | pmid = 23029166 | pmc = 3447797 | doi = 10.1371/journal.pone.0045658 | bibcode = 2012PLoSO...745658Q | doi-access = free }}</ref> The export of pfEMP1 from Maurer's cleft to RBC membrane is mediated by binding of another protein produced by the parasite called knob-associated histidine-rich protein ([[KAHRP]]). KAHRP enhances the structural rigidity of infected RBC and adhesion of PfEMP1 on the knobs.<ref>{{cite journal | vauthors = Watermeyer JM, Hale VL, Hackett F, Clare DK, Cutts EE, Vakonakis I, Fleck RA, Blackman MJ, Saibil HR | title = A spiral scaffold underlies cytoadherent knobs in Plasmodium falciparum-infected erythrocytes | journal = Blood | volume = 127 | issue = 3 | pages = 343–51 | date = January 2016 | pmid = 26637786 | pmc = 4797390 | doi = 10.1182/blood-2015-10-674002 }}</ref> It is also directly responsible for forming knobs, as indicated by the fact that ''kahrp'' gene-deficient malarial parasites do not form knobs.<ref>{{cite journal | vauthors = Crabb BS, Cooke BM, Reeder JC, Waller RF, Caruana SR, Davern KM, Wickham ME, Brown GV, Coppel RL, Cowman AF | title = Targeted gene disruption shows that knobs enable malaria-infected red cells to cytoadhere under physiological shear stress | journal = Cell | volume = 89 | issue = 2 | pages = 287–96 | date = April 1997 | pmid = 9108483 | doi = 10.1016/S0092-8674(00)80207-X | s2cid = 14042200 | doi-access = free }}</ref> To form a knob, KAHRP aggregates several membrane skeletal proteins of the host RBC, such as [[spectrin]], [[actin]], [[Ankyrin repeat|ankyrin R]], and spectrin–actin band 4.1 complex.<ref>{{cite journal | vauthors = Rug M, Prescott SW, Fernandez KM, Cooke BM, Cowman AF | title = The role of KAHRP domains in knob formation and cytoadherence of P falciparum-infected human erythrocytes | journal = Blood | volume = 108 | issue = 1 | pages = 370–8 | date = July 2006 | pmid = 16507777 | pmc = 1895844 | doi = 10.1182/blood-2005-11-4624 }}</ref> Upon arrival at the knob, PfEMP1 is attached to the spectrin network using the PHIST proteins.<ref>{{cite journal | vauthors = Oberli A, Slater LM, Cutts E, Brand F, Mundwiler-Pachlatko E, Rusch S, Masik MF, Erat MC, Beck HP, Vakonakis I | title = A Plasmodium falciparum PHIST protein binds the virulence factor PfEMP1 and comigrates to knobs on the host cell surface | journal = FASEB Journal | volume = 28 | issue = 10 | pages = 4420–33 | date = October 2014 | pmid = 24983468 | pmc = 4202109 | doi = 10.1096/fj.14-256057 | doi-access = free }}</ref><ref name=helms>{{cite journal | vauthors = Helms G, Dasanna AK, Schwarz US, Lanzer M | title = Modeling cytoadhesion of Plasmodium falciparum-infected erythrocytes and leukocytes-common principles and distinctive features | journal = FEBS Letters | volume = 590 | issue = 13 | pages = 1955–71 | date = July 2016 | pmid = 26992823 | pmc = 5071704 | doi = 10.1002/1873-3468.12142 }}</ref>

== Function ==
[[File:PfEMP cytoadhesion.png|thumb|right|Model of binding of RBC and WBC infected by ''P. falciparum'' to endothelial cells.<ref name=helms/>]]
The primary function of PfEMP1 is to bind and attach [[Red_blood_cell|RBC]]s 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 [[Duffy_binding_proteins|DBL domains]] and CIDRs.<ref>{{cite journal | vauthors = Crabb BS, Cowman AF | title = Plasmodium falciparum virulence determinants unveiled | journal = Genome Biology | volume = 3 | issue = 11 | pages = REVIEWS1031 | date = October 2002 | pmid = 12441004 | pmc = 244921 | doi = 10.1186/gb-2002-3-11-reviews1031 | doi-access = free }}</ref> DBL domains can bind to a variety of cell receptors including [[thrombospondin]] (TSP), [[complement receptor 1]] (CR1), [[Chondroitin sulfate|chondroitin sulfate A]] (CSA),<ref name=rowe09/> [[P-selectin]],<ref>{{cite journal | vauthors = Senczuk AM, Reeder JC, Kosmala MM, Ho M | title = Plasmodium falciparum erythrocyte membrane protein 1 functions as a ligand for P-selectin | journal = Blood | volume = 98 | issue = 10 | pages = 3132–5 | date = November 2001 | pmid = 11698301 | doi = 10.1182/blood.V98.10.3132 | s2cid = 8215000 }}</ref> [[endothelial protein C receptor]] (EPCR),<ref name=turner>{{cite journal | vauthors = Turner L, Lavstsen T, Berger SS, Wang CW, Petersen JE, Avril M, Brazier AJ, Freeth J, Jespersen JS, Nielsen MA, Magistrado P, Lusingu J, Smith JD, Higgins MK, Theander TG | title = Severe malaria is associated with parasite binding to endothelial protein C receptor | journal = Nature | volume = 498 | issue = 7455 | pages = 502–5 | date = June 2013 | pmid = 23739325 | pmc = 3870021 | doi = 10.1038/nature12216 | bibcode = 2013Natur.498..502T }}</ref> and [[heparan sulfate]].<ref>{{cite journal | vauthors = Angeletti D, Sandalova T, Wahlgren M, Achour A | title = Binding of subdomains 1/2 of PfEMP1-DBL1α to heparan sulfate or heparin mediates Plasmodium falciparum rosetting | journal = PLOS ONE | volume = 10 | issue = 3 | pages = e0118898 | date = 2015 | pmid = 25742651 | pmc = 4351205 | doi = 10.1371/journal.pone.0118898 | bibcode = 2015PLoSO..1018898A | doi-access = free }}</ref> The DBL domain adjacent to the head structure binds to ICAM-1.<ref>{{cite journal | vauthors = Smith JD, Craig AG, Kriek N, Hudson-Taylor D, Kyes S, Fagan T, Fagen T, Pinches R, Baruch DI, Newbold CI, Miller LH | title = Identification of a Plasmodium falciparum intercellular adhesion molecule-1 binding domain: a parasite adhesion trait implicated in cerebral malaria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 4 | pages = 1766–71 | date = February 2000 | pmid = 10677532 | pmc = 26510 | doi = 10.1073/pnas.040545897 | bibcode = 2000PNAS...97.1766S | doi-access = free }}</ref> CIDRs mainly bind to a large variety of cluster determinant 36 ([[CD36]]).<ref name=pasternak/><ref name="kraemer">{{cite journal | vauthors = Kraemer SM, Smith JD | title = A family affair: var genes, PfEMP1 binding, and malaria disease | journal = Current Opinion in Microbiology | volume = 9 | issue = 4 | pages = 374–80 | date = August 2006 | pmid = 16814594 | doi = 10.1016/j.mib.2006.06.006 }}</ref> These bindings produce the pathogenic characteristics of the parasite, such as sequestration of infected cells in different tissues,<ref name="howell">{{cite journal | vauthors = Howell DP, Levin EA, Springer AL, Kraemer SM, Phippard DJ, Schief WR, Smith JD | title = Mapping a common interaction site used by Plasmodium falciparum Duffy binding-like domains to bind diverse host receptors | journal = Molecular Microbiology | volume = 67 | issue = 1 | pages = 78–87 | date = January 2008 | pmid = 18047571 | doi = 10.1111/j.1365-2958.2007.06019.x | doi-access = free }}</ref> invasion of RBCs,<ref>{{cite journal | vauthors = Cowman AF, Crabb BS | title = Invasion of red blood cells by malaria parasites | journal = Cell | volume = 124 | issue = 4 | pages = 755–66 | date = February 2006 | pmid = 16497586 | doi = 10.1016/j.cell.2006.02.006 | s2cid = 14972823 | doi-access = free }}</ref> and clustering of infected cells by a process called rosetting.<ref name=miller7>{{cite journal | vauthors = Rowe JA, Moulds JM, Newbold CI, Miller LH | title = P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1 | journal = Nature | volume = 388 | issue = 6639 | pages = 292–5 | date = July 1997 | pmid = 9230440 | doi = 10.1038/40888 | bibcode = 1997Natur.388..292R | s2cid = 4360918 | doi-access = free }}</ref>

[[File:RBC binding site of PfEMP1.png|thumb|right|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).<ref name=Vigan/>]]

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.<ref>{{cite journal | vauthors = Baruch DI, Ma XC, Singh HB, Bi X, Pasloske BL, Howard RJ | title = Identification of a region of PfEMP1 that mediates adherence of Plasmodium falciparum infected erythrocytes to CD36: conserved function with variant sequence | journal = Blood | volume = 90 | issue = 9 | pages = 3766–75 | date = November 1997 | pmid = 9345064 | doi = 10.1182/blood.V90.9.3766 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Hsieh FL, Turner L, Bolla JR, Robinson CV, Lavstsen T, Higgins MK | title = The structural basis for CD36 binding by the malaria parasite | journal = Nature Communications | volume = 7 | pages = 12837 | date = September 2016 | pmid = 27667267 | pmc = 5052687 | doi = 10.1038/ncomms12837 | bibcode = 2016NatCo...712837H }}</ref> 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.<ref name=smith14/> 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,<ref>{{cite journal | vauthors = Howell DP, Samudrala R, Smith JD | title = Disguising itself--insights into Plasmodium falciparum binding and immune evasion from the DBL crystal structure | journal = Molecular and Biochemical Parasitology | volume = 148 | issue = 1 | pages = 1–9 | date = July 2006 | pmid = 16621067 | doi = 10.1016/j.molbiopara.2006.03.004 }}</ref> and it appears that only the DBLβ paired with C2 domain can to bind to ICAM-1.<ref name=howell/> The DBLα-CIDRγ tandem pair is the main factor for rosetting,<ref name=Vigan>{{cite journal | vauthors = Vigan-Womas I, Guillotte M, Juillerat A, Hessel A, Raynal B, England P, Cohen JH, Bertrand O, Peyrard T, Bentley GA, Lewit-Bentley A, Mercereau-Puijalon O | title = Structural basis for the ABO blood-group dependence of Plasmodium falciparum rosetting | journal = PLOS Pathogens | volume = 8 | issue = 7 | pages = e1002781 | date = 2012 | pmid = 22807674 | pmc = 3395597 | doi = 10.1371/journal.ppat.1002781 | doi-access = free }}</ref> sticking together the infected RBC with the uninfected cells, and thereby clogging of the blood vessels. This activity is performed through binding with CR1.<ref name=miller7/><ref>{{cite journal | vauthors = Stoute JA | title = Complement receptor 1 and malaria | journal = Cellular Microbiology | volume = 13 | issue = 10 | pages = 1441–50 | date = October 2011 | pmid = 21790941 | doi = 10.1111/j.1462-5822.2011.01648.x | doi-access = free }}</ref>

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.<ref>{{cite journal | vauthors = Avril M, Brazier AJ, Melcher M, Sampath S, Smith JD | title = DC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells | journal = PLOS Pathogens | volume = 9 | issue = 6 | pages = e1003430 | date = 2013 | pmid = 23825944 | pmc = 3694856 | doi = 10.1371/journal.ppat.1003430 | doi-access = free }}</ref> 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 CIDRα<sub>1.1</sub>, CIDRα<sub>1.4</sub>, CIDRα<sub>1.5</sub> and CIDRα<sub>1.7</sub>.<ref name=turner/> However, it was later shown that DC13 can bind to both ICAM-1 and EPCR.<ref>{{cite journal | vauthors = Avril M, Bernabeu M, Benjamin M, Brazier AJ, Smith JD | title = Interaction between Endothelial Protein C Receptor and Intercellular Adhesion Molecule 1 to Mediate Binding of Plasmodium falciparum-Infected Erythrocytes to Endothelial Cells | journal = mBio | volume = 7 | issue = 4 | pages = e00615–16 | date = July 2016 | pmid = 27406562 | pmc = 4958245 | doi = 10.1128/mBio.00615-16 }}</ref> EPCR is thus a potential vaccine and drug target in cerebral malaria.<ref>{{cite journal | vauthors = Lau CK, Turner L, Jespersen JS, Lowe ED, Petersen B, Wang CW, Petersen JE, Lusingu J, Theander TG, Lavstsen T, Higgins MK | title = Structural conservation despite huge sequence diversity allows EPCR binding by the PfEMP1 family implicated in severe childhood malaria | journal = Cell Host & Microbe | volume = 17 | issue = 1 | pages = 118–29 | date = January 2015 | pmid = 25482433 | pmc = 4297295 | doi = 10.1016/j.chom.2014.11.007 }}</ref>

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.<ref name="hviid"/> 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.<ref name=khunrae>{{cite journal |vauthors=Khunrae P, Dahlbäck M, Nielsen MA, Andersen G, Ditlev SB, Resende M, Pinto VV, Theander TG, Higgins MK, Salanti A | title = Full-length recombinant Plasmodium falciparum VAR2CSA binds specifically to CSPG and induces potent parasite adhesion-blocking antibodies | journal = Journal of Molecular Biology | volume = 397 | issue = 3 | pages = 826–34 | date = April 2010 | pmid = 20109466 | pmc = 3715698 | doi = 10.1016/j.jmb.2010.01.040 }}</ref> 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.<ref name="ReferenceB"/>

==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.<ref name="deistch">{{cite journal | vauthors = Deitsch KW, Chitnis CE | title = Molecular basis of severe malaria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 26 | pages = 10130–1 | date = June 2012 | pmid = 22679282 | pmc = 3387049 | doi = 10.1073/pnas.1207174109 | bibcode = 2012PNAS..10910130D | doi-access = free }}</ref> 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.<ref>{{cite book|last1=Deshmukh|first1=A. S.|last2=Srivastava|first2=S.|last3=Dhar|first3=S. K.|chapter=Plasmodium falciparum: Epigenetic Control of var Gene Regulation and Disease |series=Subcellular Biochemistry |editor1-last=Kundu|editor1-first=T. K.|title=Epigenetics: Development and Disease|volume=61|date=2013|publisher=Springer|location=Dordrecht|isbn=978-94-007-4524-7|pages=659–682|doi=10.1007/978-94-007-4525-4_28|pmid=23150271}}</ref>

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.<ref>{{cite journal | vauthors = Avril M, Tripathi AK, Brazier AJ, Andisi C, Janes JH, Soma VL, Sullivan DJ, Bull PC, Stins MF, Smith JD | title = A restricted subset of var genes mediates adherence of Plasmodium falciparum-infected erythrocytes to brain endothelial cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 26 | pages = E1782-90 | date = June 2012 | pmid = 22619321 | pmc = 3387091 | doi = 10.1073/pnas.1120534109 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Claessens A, Adams Y, Ghumra A, Lindergard G, Buchan CC, Andisi C, Bull PC, Mok S, Gupta AP, Wang CW, Turner L, Arman M, Raza A, Bozdech Z, Rowe JA | title = A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 26 | pages = E1772-81 | date = June 2012 | pmid = 22619330 | pmc = 3387129 | doi = 10.1073/pnas.1120461109 | doi-access = free }}</ref> Upon the synthesis of DC8 and DC13, their CIDR<sub>α1</sub> domains bind to EPCR, which brings about the onset of severe malaria.<ref>{{cite journal | vauthors = Bernabeu M, Smith JD | title = EPCR and Malaria Severity: The Center of a Perfect Storm | journal = Trends in Parasitology | volume = 33 | issue = 4 | pages = 295–308 | date = April 2017 | pmid = 27939609 | pmc = 5376506 | doi = 10.1016/j.pt.2016.11.004 }}</ref> The abundance of the gene products ([[Primary transcript|transcripts]]) of these PfEMP1 proteins (specifically the CIDR<sub>α1</sub> subtype transcripts) directly relates to the severity of the disease. This further indicates that preventing the interaction between CIDR<sub>α1</sub> and EPCR would be good target for a potential vaccine.<ref>{{cite journal | vauthors = Jespersen JS, Wang CW, Mkumbaye SI, Minja DT, Petersen B, Turner L, Petersen JE, Lusingu JP, Theander TG, Lavstsen T | title = Plasmodium falciparum var genes expressed in children with severe malaria encode CIDRα1 domains | journal = EMBO Molecular Medicine | volume = 8 | issue = 8 | pages = 839–50 | date = August 2016 | pmid = 27354391 | pmc = 4967939 | doi = 10.15252/emmm.201606188 }}</ref><ref>{{cite journal | vauthors = Mkumbaye SI, Wang CW, Lyimo E, Jespersen JS, Manjurano A, Mosha J, Kavishe RA, Mwakalinga SB, Minja DT, Lusingu JP, Theander TG, Lavstsen T | title = var Genes Encoding Endothelial Protein C Receptor-Binding P. falciparum Erythrocyte Membrane Protein 1 | journal = Infection and Immunity | volume = 85 | issue = 4 | pages = IAI.00841–16 | date = April 2017 | pmid = 28138022 | pmc = 5364309 | doi = 10.1128/IAI.00841-16 }}</ref> 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.<ref name=khunrae/> 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.<ref>{{cite journal | vauthors = Fried M, Duffy PE | title = Designing a VAR2CSA-based vaccine to prevent placental malaria | journal = Vaccine | volume = 33 | issue = 52 | pages = 7483–8 | date = December 2015 | pmid = 26469717 | pmc = 5077158 | doi = 10.1016/j.vaccine.2015.10.011 }}</ref>

== References ==
{{Academic peer reviewed|Q43997683|doi-access=free}}
{{Reflist|35em}}

[[Category:Plasmodium|falciparum erythrocyte]]
[[Category:Antigens]]
[[Category:Apicomplexan proteins]]