GAMA

GAMA (PF3D7_0828800) is a GPI-anchored micronemal antigen of the Plasmodium falciparum merozoite that functions as an erythrocyte-binding protein during host cell invasion (PMID:19820120, PMID:21896773). It is synthesized late in schizogony, processed into two disulfide-linked fragments, and translocated to apical micronemes, with a proportion detectable on the surface of free merozoites before the bulk of the protein is shed in soluble form after invasion (PMID:19820120). GAMA binds human erythrocytes reversibly through an epitope in its C-terminal region, engaging a nonsialylated protein receptor, and thereby contributes to the sialic acid-independent invasion pathway (PMID:19820120, PMID:21896773). Anti-GAMA antibodies inhibit invasion dose-dependently, and the pfgama gene is refractory to knockout, indicating an essential role in invasion; inhibition by antibodies raised against the 3D7 sequence is strain-specific, blocking the homologous 3D7 strain but not the heterologous FVO strain, consistent with genetic polymorphism (PMID:21896773, PMID:27692771). In the P. vivax ortholog PvGAMA, micronemal localization and Duffy-independent erythrocyte binding via a chymotrypsin-sensitive receptor are conserved (PMID:27759110). The identity of the erythrocyte receptor and the structural basis of binding have not been characterized in the available corpus.

1. 2009 Medium

   Establishing that GAMA is a micronemal, processed erythrocyte-binding protein defined it as a candidate invasion ligand rather than an uncharacterized ORF.

   Evidence Bioinformatic identification with immunoelectron microscopy, immunofluorescence, erythrocyte binding assay, and biochemical processing analysis in P. falciparum

   PMID:19820120

   Open questions at the time

   • Receptor identity on the erythrocyte not determined
   • Functional requirement in invasion not tested
   • Binding region within GAMA not mapped
2. 2011 High

   Mapping the binding activity to the C-terminal region, showing a nonsialylated protein receptor, and finding the gene refractory to knockout established GAMA as an essential ligand of the sialic acid-independent invasion pathway.

   Evidence Immunoelectron microscopy, C-terminal recombinant erythrocyte binding assay, growth inhibition assay, and attempted gene knockout in P. falciparum

   PMID:21896773

   Open questions at the time

   • Molecular identity of the nonsialylated receptor not established
   • Refractory knockout does not distinguish essentiality of invasion function from other roles
   • No structural basis for C-terminal binding
3. 2016 Medium

   Characterization of the P. vivax ortholog showed micronemal localization and Duffy-independent binding via a chymotrypsin-sensitive receptor are conserved features of the GAMA family.

   Evidence Immunofluorescence, erythrocyte binding with enzyme treatment (chymotrypsin/trypsin/neuraminidase), and antibody inhibition in P. vivax

   PMID:27759110

   Open questions at the time

   • Finding is in the P. vivax ortholog, not PF3D7_0828800 itself
   • Receptor not molecularly identified
   • Requirement of PvGAMA for invasion not shown
4. 2016 Medium

   Demonstrating strain-specific invasion inhibition connected GAMA sequence polymorphism to functional antibody escape, a key consideration for vaccine candidacy.

   Evidence Growth inhibition assay with anti-3D7 recombinant GAMA antibodies against homologous 3D7 and heterologous FVO strains of P. falciparum

   PMID:27692771

   Open questions at the time

   • Polymorphic residues responsible for strain-specificity not identified
   • Breadth across additional strains not assessed
   • In vivo protective relevance untested

• The molecular identity of the nonsialylated erythrocyte receptor for GAMA and the structural basis of its C-terminal binding remain unresolved.
• Erythrocyte receptor not identified
• No structure of the GAMA C-terminal binding region or its receptor complex
• Role of GAMA processing and shedding in invasion mechanics unknown