IMC6

IMC6 is a cytoskeletal alveolin protein of the Toxoplasma gondii inner membrane complex (IMC) that maintains parasite structural integrity and supports the subpellicular filament network (PMID:39264987, PMID:37609316). Its alveolin domain directly mediates protein-protein interactions, forming multiple binding interfaces with IMC3 and with ILP1, as mapped by photoactivatable unnatural amino acid crosslinking; the N-terminal region in particular engages the C-terminal coiled-coil domain of ILP1 (PMID:31584943, PMID:39264987, PMID:37609316). This alveolin domain alone is largely sufficient to restore IMC localization and partially sufficient for function (PMID:39264987). Disruption of IMC6 produces striking morphological defects that lead to aberrant host cell invasion and intracellular replication, while motility is only minorly affected, establishing IMC6 as essential for structural integrity rather than gliding (PMID:39264987).

1. 2019 High

   To establish how alveolin proteins physically assemble the IMC cytoskeleton, this work mapped the IMC6 binding interface, showing its N-terminal domain is necessary for binding ILP1.

   Evidence Photoactivatable unnatural amino acid crosslinking in the native intracellular environment with domain deletion analyses in T. gondii

   PMID:31584943

   Open questions at the time

   • Did not map the full set of IMC6 partners beyond ILP1
   • Functional consequence of the IMC6-ILP1 interaction for parasite viability not tested
2. 2024 High

   To determine IMC6's cellular role, gene disruption showed it is required for parasite morphology, invasion, and replication but largely dispensable for motility, separating structural from motility functions of the IMC.

   Evidence Loss-of-function gene disruption with morphology, invasion, replication, and motility phenotypic readouts in T. gondii

   PMID:39264987

   Open questions at the time

   • Molecular basis linking morphology defects to invasion/replication failure not resolved
   • Whether motility sparing reflects redundancy with other alveolins untested
3. 2024 High

   To localize the interaction and function to a specific region, deletion analyses established the alveolin domain as largely sufficient for IMC localization and partially sufficient for function, and crosslinking identified direct interfaces with both IMC3 and ILP1.

   Evidence Domain deletion with localization/functional complementation and UAA photoreactive crosslinking with mass spectrometry partner identification in T. gondii

   PMID:39264987 PMID:37609316

   Open questions at the time

   • The portion of function not restored by the alveolin domain alone is unassigned
   • Stoichiometry and higher-order filament architecture of the IMC6-IMC3-ILP1 network not resolved
4. 2025 Medium

   To position IMC6 in the temporal assembly hierarchy of the nascent IMC, timing analysis showed it is loaded onto forming daughter buds earlier than IMC1, placing IMC6 upstream in alveolin recruitment during endodyogeny.

   Evidence Expression timing and localization analysis during bud formation in T. gondii (preprint)

   PMID:40501855

   Open questions at the time

   • Preprint, single method and single lab observation
   • Mechanism determining early IMC6 recruitment unknown
   • Whether IMC6 recruitment is required for subsequent IMC1 loading not tested

• How the IMC6-nucleated alveolin network is assembled into ordered subpellicular filaments and how its structural role mechanistically constrains invasion and replication remain open.
• No structural model of the assembled filament network
• Full partner set and assembly order beyond IMC3, ILP1, and IMC1 unresolved
• Causal chain from morphology defect to invasion/replication failure uncharacterized