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John Vakonakis

John Vakonakis

University of Oxford, UK

Title: Complexes of malaria parasite and human proteins drive formation of cytoadherent assemblies at the surface of infected red blood cells

Biography

Biography: John Vakonakis

Abstract

Human red blood cells infected by the malaria parasite Plasmodium falciparum (iRBC) form dome-shaped ~120 nm-diameter protrusions on their surface, known as ‘knobs’. Knobs provide essential presentation platforms for the parasite cytoadherence receptor family PfEMP1, which binds ligands on endothelial cells of the blood vessel wall thereby immobilizing iRBC in the microvasculature. The resulting obstruction of blood vessels and disruption of normal circulation causes inflammation and tissue damage that can lead to coma and death. iRBC cytoadherence constitutes the primary mechanism driving morbidity and mortality in P. falciparum infections, which account for over 90% of all malaria-related deaths.

Despite their importance in malaria pathology the molecular mechanisms underpinning knob formation remain poorly understood. Here, I review recent progress in characterizing knob complexes formed between parasite and parasite – host proteins. Extensive flexibility is common among parasite knob components, which necessitated an integrative approach to resolve these complexes. In particular, I will focus on the development of novel in silico docking tools suitable for evaluating interactions between folded components and highly charged, very long and flexible protein segments. Our work offers the first glimpse of a molecular model for knobs.

References:

  1. 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.
  2. Warncke JD, Vakonakis I, Beck HP (2016) PHIST proteins, at the center of host cell remodeling
  3. 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.
  4. 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 co- migrates to knobs on the host cell surface. FASEB J. 28, 4420-33.
  5. Boddey JA, Cowman AF (2013) Plasmodium nesting: remaking the erythrocyte from the inside out. Annu Rev Microbiol. 67, 243-69.