ARFGAP2

PF3D7_0526200 (ARFGAP2) encodes a Plasmodium falciparum ADP-ribosylation factor GTPase-activating protein that functions as a deactivator of the parasite small GTPase PfArf1. Its catalytic domain adopts a fold similar to mammalian ARFGAPs and depends on a Zn2+ ion coordinated at a zinc-finger domain, but carries residues unique to the P. falciparum protein at the ARF1-interaction interface and at the crystal dimer interface (PMID:22102228). In vitro, the GAP domain stimulates GTP hydrolysis by PfArf1 with efficiency equivalent to human ArfGAP1 yet is insensitive to the human ArfGAP inhibitor QS11, and a distinct compound distinguishes it enzymatically from the parasite's other ArfGAP (PMID:32144363). Beyond this structural and in vitro catalytic characterization, the cellular role, trafficking context, and in vivo function of PF3D7_0526200 have not been characterized in the available corpus.

1. 2011 High

   Whether the parasite ARFGAP encoded by PF3D7_0526200 shares the architecture of mammalian ARFGAPs was unknown; solving its catalytic-domain structure established a zinc-finger-dependent fold with parasite-specific interface residues.

   Evidence X-ray crystallography of the catalytic domain by MAD phasing at 2.4 Å using the bound Zn2+ ion

   PMID:22102228

   Open questions at the time

   • Structure is of the isolated catalytic domain, not the full-length protein
   • No co-structure with PfArf1 to define the interaction interface experimentally
   • Functional consequence of the parasite-unique residues not tested
2. 2020 Medium

   Whether the PF3D7_0526200 GAP domain is catalytically active and pharmacologically distinct was unknown; in vitro assays showed it stimulates PfArf1 GTP hydrolysis at human-ArfGAP1-equivalent efficiency but is insensitive to QS11, and compound profiling demonstrated selectivity between the two parasite ArfGAPs.

   Evidence In vitro colorimetric microtiter GTPase activity assay and compound inhibition profiling

   PMID:32144363

   Open questions at the time

   • The study analyzes two P. falciparum ArfGAPs and does not always resolve which GAP domain corresponds to PF3D7_0526200
   • Activity shown in vitro only, not in parasites
   • The identity of the selectively inhibited GAP domain relative to PF3D7_0526200 is not fully established

• The cellular localization, trafficking pathway membership, in vivo function, and essentiality of PF3D7_0526200 in the parasite remain unaddressed in the available corpus.
• No cellular localization data for PF3D7_0526200
• No genetic knockout or knockdown phenotype
• No demonstration of PfArf1 regulation in living parasites