Discovery of Plasmodium falciparum SR12 as a GOLD-Domain seven transmembrane protein regulating GPCR trafficking in mammalian cells

Abstract

Considered a significant public health issue, the growing resistance to conventional antimalarials necessitates the identification of new targets for drug development. Given that G protein-coupled receptors (GPCRs) are readily druggable targets, we explored the cellular role and potential structure of a GPCR-like protein identified in the P. falciparum genome, serpentine receptor 12 (SR12). Alphafold structure analysis, coupled with molecular dynamics simulations of SR12, revealed structural similarities to the Golgi dynamics domain (GOLD)-seven-transmembrane helix protein family (GOST proteins). This family of proteins, which includes TMEM87A and the orphan GPCRs GPR180, GPR107, and GPR108, is involved in subcellular trafficking. Consistent with such a trafficking role, SR12 is mainly present in the secretory pathway when expressed in mammalian cells. Co-expression of SR12 with GPCRs PAR1 and M3R led to increased plasma membrane targeting of these receptors. SR12 expression in HEK293 cells conferred Gq-dependent calcium signaling in response to the protease activated receptor 1 (PAR1) agonist thrombin. This response was completely abrogated in cells genetically devoid of PARs (PAR KO cells), consistent with its functions as a chaperone-like protein, promoting receptor trafficking to the plasma membrane. Taken together, the data show that the Plasmodium falciparum SR12 promotes GPCR trafficking when expressed in mammalian cells. Although the physiological consequences of such activity remain to be determined, the finding revealed the presence of a GOST protein in the parasite genome.