Department of Biochemistry University of Oxford Department of Biochemistry
University of Oxford
South Parks Road
Oxford OX1 3QU

Tel: +44 (0)1865 613200
Fax: +44 (0)1865 613201
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Malaria is a parasitic disease virtually absent in the developed world, but that still affects developing countries strongly. Most malaria deaths are caused by a single parasite species, Plasmodium falciparum, and many can be attributed to obstruction of small blood vessels in tissues by red blood cell clumps. Cytoadherence of infected erythrocytes is mediated by a system unique to P. falciparum that includes the PfEMP1 protein family and other parasite components.

Our research focuses on how parasite proteins exported to the host cell endow the erythrocyte with adhesion characteristics, as well as alter its shape and mechanical properties. Overall the parasite exports ~500 proteins, many of which are unique to Plasmodia. Despite being putative targets for therapeutic intervention, ~75% of these proteins have no functional annotation. We try to understand their function by studying the interactions between parasite-parasite and parasite-host components using structural biology and biophysics. We collaborate closely with Prof. Hans-Peter Beck (cell biology, SwissTPH) in these efforts.

We previously determined the structure of the intracellular domain of PfEMP1, the main parasite adhesion receptor, by NMR and SAXS. This segment, termed ATS, mediates adhesion forces from outside the infected erythrocyte to the cytoskeleton. Our analysis suggested that ATS is largely flexible in solution with only a single well-folded core. Yet, ATS is highly conserved. We showed that some of the conserved but flexible segments of ATS form complexes with members of the parasite PHIST protein family, and determined the first structures and complexes of PHIST proteins. A specific PHIST member, PFE1605w (also known as LyMP) was shown to strengthen cytoadherence by linking the PfEMP1 adhesion receptor with the erythrocyte cytoskeleton.


We currently study how parasite components interact with the erythrocyte cytoskeleton, and in so doing form protrusions on the host cell surface (knobs) on which PfEMP1 locates. We use computational modelling, as well as more traditional schematics, to visualise what knobs look like.


Relevant publications

Cutts EE, Laasch N, Reiter DM, Trenker R, Slater LM, Stansfeld PJ, Vakonakis I (2017) Structural analysis of P. falciparum KAHRP and PfEMP1 complexes with host erythrocyte spectrin suggests a model for cytoadherent knob protrusions. PLoS Pathog 13, e1006552.


Oberli A, Zurbrügg L, Rusch S, Brand F, Butler ME, Day JL, Cutts EE, Lavstsen T, Vakonakis I, Beck HP (2016) Plasmodium falciparum PHIST Proteins Contribute to Cytoadherence and Anchor PfEMP1 to the Host Cell Cytoskeleton. Cell Microbiol 18, 1415-28.


Warncke JD, Vakonakis I, Beck HP (2016) Plasmodium Helical Interspersed Subtelomeric (PHIST) Proteins, at the Center of Host Cell Remodeling. Microbiol Mol Biol Rev 80, 905-27.


Watermeyer JM, Hale VL, Hackett F, Clare DK, Cutts EE, Vakonakis I, Fleck RA, Blackman MJ, Saibil HR (2016) A spiral scaffold underlies cytoadherent knobs in Plasmodium falciparum-infected erythrocytes. Blood 127, 343-51.


Oberli A, Slater LM, Cutts E, Brand F, Mundwiler-Pachlatko E, Rusch S, Masik MFG, Erat MC, Beck HP, Vakonakis I (2014) A Plasmodium falciparum PHIST protein binds the virulence factor PfEMP1 and comigrates to knobs on the host cell surface. FASEB J 28, 4420-4433.


Mayer C, Slater L, Erat MC, Konrat R, Vakonakis I (2012) Structural analysis of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) intracellular domain reveals a conserved interaction epitope. J Biol Chem. 287, 7182-9.






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