DPY19

PF3D7_0806200 (DPY19) is a tryptophan C-mannosyltransferase of P. falciparum that catalyzes C-glycosylation of the thrombospondin type-1 repeat (TSR) domains of TRAP/MIC2-family micronemal adhesins (PMID:29432542, PMID:35906227). When expressed in C-mannosylation-deficient mammalian cells it modifies TSR domains, and in vitro it transfers mannose to a WXXWXXC peptide but is inactive on a short WXXW peptide, defining an acceptor specificity distinct from C. elegans and mammalian C-mannosyltransferases (PMID:29432542). In the parasite, DPY19 resides in the endoplasmic reticulum, where deletion (ΔDPY19) abolishes C-glycosylation of TSR-domain proteins including MTRAP and CTRP and destabilizes TRAP adhesin family members, implicating the enzyme in TSR-protein quality control (PMID:35906227). DPY19 is dispensable for asexual blood-stage growth even under ER stress (PMID:31559936), but it is required during sexual development: its loss impairs gametocyte egress and exflagellation and abrogates ookinete infectivity of mosquitoes, and genetic complementation restores C-mannosylation, ookinete infectivity, and sporozoite production (PMID:35906227). Beyond these findings, no further mechanistic detail on DPY19 has been characterized in the available corpus.

1. 2018 High

   Establishing whether PF3D7_0806200 is a functional C-mannosyltransferase and what it recognizes defined the enzyme's catalytic identity and an unexpected acceptor specificity.

   Evidence Heterologous expression in C-mannosylation-deficient mammalian cells plus in vitro assay with WXXWXXC versus WXXW peptides

   PMID:29432542

   Open questions at the time

   • Endogenous substrate repertoire in the parasite not defined by the peptide assay
   • Structural basis for the WXXWXXC preference over WXXW not determined
   • Catalytic residues and mannose-donor requirements not mapped
2. 2019 Medium

   Testing whether DPY19 is required for asexual replication showed the enzyme is dispensable at this stage, narrowing where its function is critical.

   Evidence CRISPR/Cas9 gene disruption with in vitro growth assays under normal and ER-stress conditions

   PMID:31559936

   Open questions at the time

   • Does not address sexual-stage or transmission phenotypes
   • No direct assessment of C-mannosylation status in the knockout in this study
3. 2022 High

   Linking DPY19 to ER localization, TSR-protein C-glycosylation, and sexual-stage biology established its physiological role in adhesin quality control and mosquito transmission.

   Evidence CRISPR/Cas9 knockout and genetic complementation, 4D lattice light-sheet imaging of gametogenesis, mass spectrometry of C-mannosylation, and subcellular localization

   PMID:35906227

   Open questions at the time

   • Mechanism by which loss of C-mannosylation destabilizes TRAP-family proteins not resolved
   • How defective TSR modification mechanistically blocks gametocyte egress and exflagellation not defined
   • Full inventory of endogenous DPY19 substrates beyond MTRAP and CTRP unknown

• The structural and mechanistic basis for DPY19's distinct acceptor specificity and how its modification enforces adhesin stability during transmission remain open.
• No structural model or catalytic mechanism reported
• Full substrate set and the step at which unmodified TSR proteins are degraded unresolved