MIC7

TgMIC7 is a transmembrane microneme protein of Toxoplasma gondii that participates in the initial steps of host cell invasion (PMID:11861763, PMID:32618271). Its ectodomain contains multiple EGF-like domains and is anchored by a transmembrane-spanning segment, while its short cytoplasmic tail encodes the sorting signals that direct the protein to the micronemes (PMID:11861763). MIC7 is N-myristoylated at its N-terminus, and this lipidated N-terminus is oriented toward the microneme lumen, indicating an unconventional entry into the secretory pathway that places a lipid modification on the luminal face (PMID:32618271). Both MIC7 and its N-myristoylation are required for efficient host cell invasion, acting during the interaction with and penetration of the host cell membrane (PMID:32618271). Beyond these findings, the molecular partners and precise biochemical mechanism of MIC7 have not been characterized in the available corpus.

1. 2002 Medium

   Established MIC7 as a bona fide microneme protein and defined how it is trafficked, answering where the protein resides and what directs it there.

   Evidence Protein topology characterization and mutational analysis of the cytoplasmic tail with immunofluorescence/subcellular fractionation in T. gondii

   PMID:11861763

   Open questions at the time

   • The specific sorting-machinery components that recognize the cytoplasmic tail were not identified
   • No functional role for the EGF-like domains was tested
2. 2002 Low

   Placed MIC7 in the bradyzoite stage, framing it as a potential stage-specific escorter analogous to tachyzoite MIC6/MIC8.

   Evidence Stage-specific transcriptional profiling of tachyzoite versus bradyzoite stages in T. gondii

   PMID:11861763

   Open questions at the time

   • Escorter activity was inferred from expression and analogy, not demonstrated by any direct functional experiment
   • No bradyzoite-stage invasion phenotype was measured
   • Cargo escorted by MIC7, if any, was not identified
3. 2020 High

   Revealed that MIC7 carries a luminally-oriented N-myristoyl modification, answering how a lipid-modified microneme protein enters the secretory pathway and pointing to an unconventional trafficking route.

   Evidence Chemoproteomic N-myristoylation profiling (metabolic labeling with alkyne-myristate, click chemistry, mass spectrometry) combined with topology analysis in T. gondii

   PMID:32618271

   Open questions at the time

   • The enzyme(s) and mechanism producing luminal orientation of the myristoyl group are not defined
   • How the lipid modification affects trafficking or folding was not resolved
4. 2020 Medium

   Demonstrated that MIC7 and its myristoylation are functionally required for invasion, connecting the protein and its lipid modification to the entry step of the parasite lifecycle.

   Evidence Genetic loss-of-function (knockout/conditional depletion) plus myristoylation-site mutagenesis with invasion/penetration readout in T. gondii

   PMID:32618271

   Open questions at the time

   • The molecular event during membrane penetration that MIC7 mediates was not identified
   • Host-cell binding partners or interacting parasite proteins were not defined
   • Whether the invasion role operates in bradyzoites specifically was not tested

• The direct binding partners, escorted cargo, and biochemical function of MIC7 during membrane penetration remain undefined.
• No molecular partner or receptor for MIC7 has been identified
• The proposed escorter activity has not been directly tested
• No structural model of the EGF-domain ectodomain exists in the corpus