Abstract
AbstractInfection with the Apicomplexan protozoanToxoplasma gondiican be life-threatening in immunocompromised hosts. Transmission frequently occurs through the oral ingestion ofT. gondiibradyzoite cysts, which transition to tachyzoites, disseminate, and then form cysts containing bradyzoites in the central nervous system, resulting in latent infection. There are currently no effective treatments to cure latent infection. Bradyzoites are encapsulated by a cyst wall that is critical for immune evasion, survival, and transmission. Cyst wall rigidity is influenced by the O-glycosylation of the mucin domain of the cyst wall protein CST1 by mucin-type O-glycosyltransferases (GalNAc-Ts). Here, we report the first structures of a protozoan GalNAc-T,T.gondii-GalNAc-T3 in the apo state and in complex with glycopeptide substrates. The structures reveal features that are strictly conserved in Apicomplexan homologues ofT.gondii-GalNAc-T3, including a unique 2ndmetal binding site that is coupled to substrate binding and enzymatic activityin vitroand cyst wall O-glycosylation inT. gondii. Additional structural features illustrate the divergence of GalNAc-Ts from parasite to host and highlight multiple druggable sites inT.gondii-GalNAc-T3 and its homologues in Apicomplexa that are responsible for a wide range of parasitic diseases.
Publisher
Cold Spring Harbor Laboratory