PF3D7_1251200

PfCoronin (PF3D7_1251200) is a WD40/β-propeller actin filament-binding protein that acts as a regulator of PfActin dynamics across the Plasmodium life cycle (PMID:9883894, PMID:26187846). It directly binds pre-formed F-actin through its N-terminal β-propeller domain and promotes formation of parallel actin filament bundles, and it associates with membranes, likely through PI(4,5)P2 (PMID:9883894, PMID:26187846). In P. falciparum, PfCoronin localizes to the parasite plasma membrane, the digestive vacuole membrane, and a preDV compartment implicated in hemoglobin trafficking, and it interacts with PfActin to support ring-stage endocytic hemoglobin uptake (PMID:38187525, PMID:40964400). In P. berghei sporozoites, coronin regulates gliding motility: calcium-triggered, actin-dependent relocalization of coronin to the cell rear initiates motility, and coronin overexpression can rescue penetration defects caused by actin subdomain mutations, establishing it as a functional actin filament regulator (PMID:27409081, PMID:30011270). PfCoronin is dispensable for parasite viability, but resistance-associated mutations disrupt its interaction with PfActin and its ring-stage localization, impairing preDV development and reducing hemoglobin acquisition; the resulting reduction in heme-dependent artemisinin activation confers partial ART resistance through a pathway parallel to but distinct from PfKelch13 (PMID:30420498, PMID:38187525, PMID:40964400).

1. 1998 Medium

   Establishing whether the WD-repeat coronin homolog in P. falciparum actually engages the actin cytoskeleton was the first step in assigning it a function.

   Evidence Co-sedimentation of recombinant protein with exogenous F-actin and Triton fractionation of schizont extracts

   PMID:9883894

   Open questions at the time

   • Binding shown with exogenous, not native parasite, F-actin
   • No domain mapping of the actin-binding region
   • No cellular localization or phenotype
2. 2015 High

   Beyond simple binding, it was unclear how PfCoronin engages actin and where it acts, so the domain requirement and subcellular context were defined.

   Evidence Recombinant β-propeller F-actin sedimentation and TIRF bundling assays, phospholipid binding, and imaging of a tagged parasite line

   PMID:26187846

   Open questions at the time

   • Functional consequence of bundling in vivo not tested
   • PI(4,5)P2 interaction inferred, not directly proven in situ
   • Role limited to invasive merozoite stage in this study
3. 2016 High

   Whether coronin has a required in vivo role was addressed genetically, linking it to actin-dependent gliding motility and its signaling control.

   Evidence Genetic knockout in P. berghei with live imaging, calcium and cAMP/PKA perturbation

   PMID:27409081

   Open questions at the time

   • Direct molecular link between PKA and coronin-dependent filament disassembly not defined
   • Findings are in P. berghei sporozoites, not P. falciparum blood stages
   • Mechanism of calcium-triggered relocalization unresolved
4. 2018 Medium

   To place coronin causally within actin regulation, whether it could compensate for defective actin dynamics was tested.

   Evidence Coronin overexpression rescue of actin subdomain-mutant P. berghei parasites in a mosquito organ penetration assay

   PMID:30011270

   Open questions at the time

   • Molecular basis of rescue not defined
   • Restricted to motile mosquito stages
   • Does not address blood-stage function
5. 2018 High

   The clinical significance of PfCoronin emerged when it was asked whether mutations alone could reduce artemisinin susceptibility independent of PfKelch13.

   Evidence In vitro DHA selection, whole-genome sequencing, and CRISPR/Cas9 allelic replacement with ring-stage survival assay readout

   PMID:30420498

   Open questions at the time

   • Mechanism connecting mutations to resistance not established
   • Cellular process affected unknown at this stage
   • Relationship to PfKelch13 pathway undefined
6. 2024 High

   The mechanism of PfCoronin-mediated resistance was resolved by tying the protein to PfActin, hemoglobin-trafficking compartments, and endocytosis.

   Evidence Co-immunoprecipitation of PfCoronin–PfActin, live/fixed localization, CRISPR/Cas9 introduction of resistance mutations, and hemoglobin uptake and preDV morphology assays (preprint)

   PMID:38187525

   Open questions at the time

   • Preprint, not peer-reviewed
   • How preDV compartment couples to the digestive vacuole not fully defined
   • Quantitative link from reduced uptake to heme-dependent drug activation not directly measured
7. 2025 High

   The genetic requirement and pathway relationship were formalized, showing PfCoronin is dispensable and acts in a ring-stage endocytic pathway that converges with PfKelch13 on heme availability.

   Evidence Genetic knockout for dispensability, allelic replacement, PfCoronin–PfActin co-immunoprecipitation, localization imaging, hemoglobin uptake assays, and epistasis with PfKelch13 (preprint)

   PMID:40964400

   Open questions at the time

   • Preprint, not peer-reviewed
   • Distinct cellular regions of PfCoronin vs PfKelch13 action not spatially resolved in detail
   • Structural basis for mutation-driven loss of PfActin interaction unknown

• How resistance-associated substitutions in the β-propeller structurally disrupt PfActin binding and preDV endocytosis, and how this quantitatively limits heme-dependent artemisinin activation, remains open.
• No structure of mutant PfCoronin–PfActin complex
• Direct measurement of heme flux downstream of reduced hemoglobin uptake absent
• Mechanistic overlap with PfKelch13 endocytosis not molecularly defined