MIC2 (Toxoplasma gondii ME49; UniProt S8F9G8; TGME49_201780) - curation notes

Note: automated deep research was unavailable in this environment (Falcon
authentication failed; OpenAI key invalid). These notes are a manual literature review
built from the UniProt record and primary papers cached in publications/, identified
by PubMed searches. No *-deep-research-*.md file exists for this gene.

2026-10-14 - initial review

Sequence / domain architecture (UniProt S8F9G8, TrEMBL, unreviewed)

• 769 aa; predicted signal peptide 1-26; VWFA (integrin-like A/I) domain 76-263;
  six TSP1 repeats (Pfam PF00090 x6); C-terminal hydrophobic segment
  (~GIAGAIAGGVIGGLILLGAAGGA) followed by a short acidic cytoplasmic tail ending in
  ...DDDSDMWME (penultimate Trp typical of TRAP-family tails). UniProt does not annotate
  a TM segment; its SUBCELLULAR LOCATION "Secreted" is an ARBA rule inference.
• PANTHER places it in PTHR22906 "PROPERDIN" only because of the TSR repeats; MIC2 is
  not a complement regulator. The single GOA row (extracellular region, IEA from
  UniProt SubCell) derives from the ARBA "Secreted" call.

Identity and microneme localization

• PMID:9084040
• PMID:9084040
• TSR and integrin-A-like domains noted at cloning: PMID:9084040
• Domain architecture from crystal structures: PMID:24639528

Type I transmembrane adhesin; complex with M2AP

• PMID:14670959
• Stoichiometry disputed: hexamer (native gels) PMID:14670959 versus 1:1 ectodomain
  monomer PMID:24639528.
• M2AP is needed for MIC2 trafficking and secretion PMID:12727875; conversely MIC2 loss mistraffics M2AP
  PMID:16933991.

Secretion, surface translocation, shedding (localization dynamics)

• Apical secretion, rearward translocation and rhomboid cleavage:
  PMID:15753289
• Intramembrane shedding: PMID:14982962; MPP1/MPP2 processing PMID:10799515
• Hence the ectodomain does end up in the extracellular milieu (the "excreted-secreted
  antigen" fraction; PMID:16933991), but
  the functional locations are the microneme (storage) and the parasite cell surface
  (adhesion). "Extracellular region" is therefore true but peripheral.

Molecular function: adhesin

• A-domain binds heparin: PMID:15003840;
  binding is MIDAS-independent and multimeric.
• Binds host ICAM-1: PMID:15760456
• Cytoplasmic tail binds aldolase, linking adhesin to F-actin/motor:
  PMID:12718875;
  acidic clusters needed PMID:16923803.
• Best GO MF: GO:0098631 cell adhesion mediator activity (binding by a surface
  adhesion protein to a molecule on another cell or substrate to mediate adhesion).
  GO:0008201 heparin binding is directly shown for the recombinant A-domain (in vitro).

Biological process: attachment, gliding, invasion

• Conditional knockdown (Huynh & Carruthers 2006): PMID:16933991;
  PMID:16933991
• Clean conditional KO (Andenmatten 2013): MIC2 not essential PMID:23263690
• Null mutant analysis (Gras 2017) revises the model: role mainly in attachment, not in
  sustaining motility/penetration; mild virulence attenuation only.
  PMID:28630943
  PMID:28630943
• Interpretation: MIC2 itself performs the adhesion step (it is the adhesin, binding
  host ligands while gripping the motor via aldolase), so "adhesion of symbiont to host
  cell" (GO:0044650) is a participation annotation, not mere necessity. Gliding
  motility: GO:0071980 "cell surface adhesin-mediated gliding motility" is defined by
  exactly this mechanism; MIC2 contributes to helical gliding/twirling (both knockdown
  and KO). Invasion (GO:0085017): MIC2 contributes via attachment at the start of entry;
  the KO shows invasion still occurs, so non-core.
• Virulence: knockdown claimed avirulent (PMID:16933991) but KO remains lethal in mice
  (PMID:28630943). Do not annotate virulence.

Curation decisions

• GO:0005576 extracellular region (IEA, SubCell): KEEP_AS_NON_CORE - shed ectodomain is
  released into the medium, but primary locations are microneme and cell surface.
• NEW: GO:0020009 microneme (IDA PMID:9084040); GO:0009986 cell surface (IDA
  PMID:15753289); GO:0098631 cell adhesion mediator activity (PMID:15760456,
  PMID:15003840); GO:0008201 heparin binding (IDA PMID:15003840); GO:0044650 adhesion of
  symbiont to host cell (IMP PMID:28630943, PMID:16933991); GO:0071980 cell surface
  adhesin-mediated gliding motility (IMP PMID:16933991, PMID:28630943).
• GO:0085017 entry into host cell by a symbiont-containing vacuole: considered; added as
  NEW but flagged non-core because KO invasion defect is secondary to attachment.
• No host-process ("symbiont-mediated perturbation of host ...") terms: MIC2 does not
  modulate host processes; ICAM-1 engagement is adhesion.
• PANTHER PTHR22906 "properdin" family membership should not be propagated to complement
  terms (none present now).