Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Nat Commun. 2023 Sep 14;14(1):5703. doi: 10.1038/s41467-023-40885-8.
Tryptophan Rich Antigens (TRAgs) are encoded by a multi-gene family found in all Plasmodium species, but are significantly expanded in P. vivax and closely related parasites. We show that multiple P. vivax 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 Plasmodium 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 P. knowlesi, PKNH_1300500, impacts invasion in reticulocytes, suggesting a role during this essential process. Together, this work defines an emerging molecular function for the Plasmodium TRAg family.
色氨酸丰富抗原（TRAgs）由一个多基因家族编码，存在于所有疟原虫物种中，但在间日疟原虫和密切相关的寄生虫中显著扩张。我们表明，多个间日疟原虫 TRAgs 在裂殖子表面表达，其中一个，PVP01_0000100 与红细胞结合具有强烈的网织红细胞偏好。使用 X 射线晶体学，我们解决了 PVP01_0000100 C 末端色氨酸丰富结构域的结构，该结构定义了 TRAg 家族，揭示了一个三螺旋束，该结构在整个疟原虫中保守，并且与涉及膜重塑的脂质结合 BAR 结构域具有结构同源性。生化分析证实，PVP01_0000100 C 末端结构域具有脂质结合活性，优先结合神经节苷脂，一种存在于质膜外层的糖脂。在食蟹猴疟原虫 PKNH_1300500 中删除假定的同源物会影响网织红细胞的入侵，表明在这个基本过程中具有作用。总之，这项工作定义了疟原虫 TRAg 家族一个新的分子功能。
