SR10

SR10 (PF3D7_1215900) is a serpentine/G-protein-coupled-like receptor of Plasmodium that functions to time and coordinate the intra-erythrocytic developmental cycle (IDC) with host daily rhythms and to sustain both asexual replication and gametocyte production (PMID:32488076, PMID:32890576). SR10 transcription oscillates with a 24 h period, and its genetic disruption in the rodent parasite P. chabaudi shortens the IDC by 2–3 h while perturbing DNA replication and ubiquitin/proteasome pathways, establishing it as a regulator of developmental cycle duration (PMID:32488076). In P. falciparum, SR10 is expressed in asexual and sexual blood stages and localizes to the endoplasmic reticulum, where it physically associates with the ER-resident protein ERC; its loss impairs intraerythrocytic replication and strongly reduces gametocyte numbers (PMID:32890576). As a receptor, SR10 couples to human Gi/Gq proteins upon activation by antimalarial drugs (chloroquine, dihydroartemisinin, piperaquine-tetraphosphate, primaquine diphosphate) acting as agonists and by the host peptide bradykinin as an endogenous agonist, with ligand-binding sites and activating conformational changes resolved by cryo-EM, mutagenesis, and FlAsH-BRET (PMID:41280702).

1. 2020 Medium

   Whether any parasite factor sets the pace of the intra-erythrocytic cycle and aligns it to host rhythms was unresolved; disruption of SR10 defined it as a timekeeping regulator.

   Evidence In vivo loss-of-function disruption in P. chabaudi with transcriptomic and time-series rhythmicity profiling

   PMID:32488076

   Open questions at the time

   • Molecular mechanism linking SR10 to IDC length is not defined
   • How SR10 impinges on DNA replication and ubiquitin/proteasome pathways is unknown
   • Rodent-parasite phenotype not directly demonstrated for the IDC-timing role in P. falciparum
2. 2020 Medium

   The subcellular site of SR10 action and its stage-specific requirement were unknown; localization and disruption studies placed it at the ER and tied it to both replication and sexual commitment.

   Evidence Co-localization and reciprocal Co-IP with ER-resident ERC, plus gene disruption scored for replication and gametocyte counts in P. falciparum

   PMID:32890576

   Open questions at the time

   • Functional consequence of the SR10–ERC association is uncharacterized
   • How an ER-localized receptor controls gametocytogenesis is unresolved
   • Single-lab evidence for the ER localization
3. 2025 High

   Whether SR10 is a bona fide signaling receptor and what activates it were open; structural and biochemical reconstitution established it as a GPCR-like receptor coupling to Gi/Gq and identified drug and peptide agonists.

   Evidence Biochemical reconstitution, cryo-EM, mutagenesis, FlAsH-BRET, and proteomic profiling of ligands in P. falciparum

   PMID:41280702

   Open questions at the time

   • Endogenous downstream signaling pathway in the parasite is not mapped
   • Physiological relevance of bradykinin activation in vivo is not established
   • Whether drug agonism relates to antimalarial mechanism of action is unaddressed

• How ligand binding and Gi/Gq coupling mechanistically connect to IDC timing, ER function, DNA replication, and gametocyte production remains unresolved.
• No signaling-to-phenotype causal chain linking receptor activation to developmental control
• Native endogenous agonist and its source in the host–parasite context unconfirmed
• No integration of the ER localization with GPCR-like signaling model