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The structure of a Plasmodium vivax Tryptophan Rich Antigen domain suggests a lipid binding function for a pan-Plasmodium multi-gene family

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Kundu, Prasun 
Naskar, Deboki 
McKie, Shannon J 
Dass, Sheena 
Kanjee, Usheer 


jats:titleAbstract</jats:title>jats:pTryptophan Rich Antigens (TRAgs) are encoded by a multi-gene family found in all jats:italicPlasmodium</jats:italic> species, but are significantly expanded in jats:italicP. vivax</jats:italic> and closely related parasites. We show that multiple jats:italicP. vivax</jats:italic> TRAgs are expressed on the merozoite surface and that one, PVP01_0000100 binds red blood cells with a strong preference for reticulocytes. Using X-ray crystallography, we solved the structure of the PVP01_0000100 C-terminal tryptophan rich domain, which defines the TRAg family, revealing a three-helical bundle that is conserved across jats:italicPlasmodium</jats:italic> and has structural homology with lipid-binding BAR domains involved in membrane remodelling. Biochemical assays confirm that the PVP01_0000100 C-terminal domain has lipid binding activity with preference for sulfatide, a glycosphingolipid present in the outer leaflet of plasma membranes. Deletion of the putative orthologue in jats:italicP. knowlesi</jats:italic>, jats:italicPKNH_1300500</jats:italic>, impacts invasion in reticulocytes, suggesting a role during this essential process. Together, this work defines an emerging molecular function for the jats:italicPlasmodium </jats:italic>TRAg family.</jats:p>


Acknowledgements: We would like to thank Prof. Gavin J. Wright for his help during the construct designing for expression vectors and for providing the HEK 293E cell line for protein expression. Dr. Robert W. Moon for providing the CRISPR Cas9 plasmid and Plasmodium knowlesi A1.H1 line. Dr. Reiner Schulte, Gabriela Grondys-Kotarba and Chiara Cossetti of the CIMR Flow Cytometry facility for providing required training and assistance during the flow cytometry experiments. We also like to convey our thanks to Matthew Gratian and Mark Bowen for providing training and data acquisition in LSM880 confocal microscope with Airyscan setting. We are grateful to Alison Kemp for her guidance to use the CRISPR Cas9 system. Ellen Knuepfer for the kind donation of Rat anti-PkMSP1-19 serum. We thank Stephen Graham for help with crystallographic model building. We acknowledge Diamond Light Source for time on beamline I04 under proposal MX21426. This work was funded by the National Institutes of Health (R01AI137154) and the Wellcome Trust (220266/Z/20/Z). J.E.D. and S.J.M. are supported by a Wellcome Trust Senior Research Fellowship (219447/Z/19/Z) awarded to J.E.D. As this research was funded in part by the Wellcome Trust, for the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.


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Nature Communications

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Springer Science and Business Media LLC
Wellcome Trust (Wellcome) (222323/Z/21/Z, 219447/Z/19/Z, 219447/Z/19/Z)
U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (R01AI137154)