{"gene":"PF3D7_1203200","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2014,"finding":"P. falciparum SRP14 is one of six polypeptides (SRP9, SRP14, SRP19, SRP54, SRP68, SRP72) that compose the P. falciparum SRP ribonucleoprotein complex together with a 303 nt SRP RNA. GFP-tagged SRP14 expressed in transgenic parasites localizes to both nucleus and cytoplasm (nucleo-cytoplasmic shuttling), and ivermectin (an importin α/β-mediated nuclear import inhibitor) blocks nuclear import of PfSRP polypeptides including SRP14 at submicromolar concentrations, killing the parasites.","method":"Transgenic P. falciparum lines expressing SRP14-GFP chimeric proteins; fluorescence co-localization microscopy; pharmacological inhibition with ivermectin","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with GFP fusion in live parasites and functional consequence (parasite killing) via pharmacological inhibition, single lab with two orthogonal methods","pmids":["24434517"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"The P. falciparum SRP14 protein forms a heterodimer with SRP9 (PfSRP9/14) as part of the Alu domain. SAXS analysis shows the PfSRP9/14 heterodimer adopts a compact, folded globular conformation (Dmax ~7.2 nm), and the ab initio envelope accommodates the human SRP9/14 heterodimer crystal structure. PfSRP14 contains an extended internal loop L1 (residues 35–70) absent in human SRP14. The PfAlu domain (comprising PfSRP9/14 and PfAlu RNA) adopts an open Y-shaped conformation—distinct from the canonical closed conformation—and P. falciparum cytoplasmic ribosomes bind both the open PfAlu and closed human Alu domains with nanomolar affinity.","method":"NMR, SAXS, and cryo-EM structural analyses of recombinant PfSRP9/14 heterodimer and PfAlu RNA expressed in E. coli; ribosome binding affinity measurements","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal structural methods (NMR, SAXS, cryo-EM) with functional validation (ribosome binding affinity) in a single rigorous study","pmids":["34017052"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2004,"finding":"Bioinformatic genome analysis identified SRP14 and SRP9 homologs in P. falciparum (SRP14 previously annotated as a hypothetical protein, accession PFL0160w), establishing SRP14 as a component of the P. falciparum SRP Alu domain alongside SRP9.","method":"Comparative genomic/bioinformatic analysis of protozoan genome sequences","journal":"BMC genomics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no direct biochemical experiment performed on the P. falciparum protein","pmids":["14720308"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"P. falciparum SRP14 (PF3D7_1203200) forms a compact heterodimer with SRP9 as the protein component of the SRP Alu domain; unlike its human counterpart, the PfSRP9/14 heterodimer contains an extended internal loop (L1) and the intact PfAlu domain adopts an open Y-shaped conformation that is recognized with nanomolar affinity by P. falciparum ribosomes; in live parasites, SRP14 undergoes nucleo-cytoplasmic shuttling via importin α/β-dependent nuclear import, which can be blocked by ivermectin."},"narrative":{"mechanistic_narrative":"PF3D7_1203200 (SRP14) is the protein component of the Alu domain of the P. falciparum signal recognition particle, a ribonucleoprotein complex of six polypeptides (SRP9, SRP14, SRP19, SRP54, SRP68, SRP72) assembled on a 303 nt SRP RNA [PMID:24434517]. SRP14 forms a compact, folded globular heterodimer with SRP9 (PfSRP9/14), which together with the PfAlu RNA constitutes the PfAlu domain; unlike its human counterpart, PfSRP14 carries an extended internal loop L1 (residues 35–70), and the intact PfAlu domain adopts an open Y-shaped conformation rather than the canonical closed form, yet is bound by P. falciparum cytoplasmic ribosomes with nanomolar affinity [PMID:34017052]. In live parasites, GFP-tagged SRP14 shuttles between nucleus and cytoplasm, and its nuclear import is importin α/β-dependent and blocked by ivermectin at submicromolar concentrations, which kills the parasite [PMID:24434517]. Beyond its structural role in the Alu domain, its ribosome-binding property, and its nucleo-cytoplasmic trafficking, no further mechanistic detail on PF3D7_1203200 has been characterized in the available corpus.","teleology":[{"year":2004,"claim":"Before any experimental work, it was unknown whether P. falciparum even encoded an SRP Alu-domain protein; genome analysis answered this by identifying an SRP14 homolog, establishing the gene as a candidate SRP component.","evidence":"Comparative genomic/bioinformatic analysis of protozoan genomes, annotating the former hypothetical protein PFL0160w","pmids":["14720308"],"confidence":"Low","gaps":["Computational prediction only; no biochemical validation of the P. falciparum protein","Did not establish whether the predicted protein assembles into an SRP complex or binds RNA"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"It was unknown where SRP14 resides in the parasite or whether its trafficking is druggable; live-parasite imaging placed SRP14 in a six-polypeptide SRP complex and showed importin-dependent nucleo-cytoplasmic shuttling that ivermectin blocks, linking SRP14 trafficking to parasite viability.","evidence":"Transgenic SRP14-GFP P. falciparum lines with co-localization microscopy and pharmacological ivermectin inhibition","pmids":["24434517"],"confidence":"Medium","gaps":["Ivermectin acts on general importin α/β import, so the killing effect is not proven to be SRP14-specific","Functional role of nuclear localization for an SRP protein remains undefined","Assembly stoichiometry and order within the SRP complex not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"The structural basis of the parasite Alu domain and how it differs from the human counterpart was unknown; multi-method structural analysis showed PfSRP14 forms a globular heterodimer with SRP9, carries a unique extended L1 loop, and yields an open Y-shaped Alu domain that nonetheless binds ribosomes with nanomolar affinity.","evidence":"NMR, SAXS, and cryo-EM of recombinant PfSRP9/14 and PfAlu RNA from E. coli, with ribosome-binding affinity measurements","pmids":["34017052"],"confidence":"High","gaps":["Functional consequence of the open Y-shaped conformation for translational arrest was not tested","Role of the parasite-specific L1 loop not experimentally dissected","Structure of SRP14 within the full six-protein SRP was not determined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"Whether the SRP14-dependent Alu domain executes canonical elongation arrest during co-translational targeting in P. falciparum, and whether SRP14 itself is essential and druggable independent of general importin inhibition, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No functional assay directly linking SRP14 to translational arrest or protein targeting in the parasite","No SRP14-specific genetic knockout/knockdown phenotype reported","Physiological significance of nuclear localization for SRP14 unestablished"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Signal recognition particle (SRP9/SRP14/SRP19/SRP54/SRP68/SRP72 + 303 nt SRP RNA)","PfSRP9/14 Alu-domain heterodimer"],"partners":["SRP9","PFALU RNA","P. FALCIPARUM CYTOPLASMIC RIBOSOME","IMPORTIN Α/Β IMPORT MACHINERY"],"other_free_text":["PfSRP14 contains a parasite-specific extended internal loop L1 (residues 35–70) absent in human SRP14 [#1]","The intact PfAlu domain adopts an open Y-shaped conformation distinct from the canonical closed form yet binds ribosomes with nanomolar affinity [#1]","Ivermectin blocks importin α/β-dependent nuclear import of SRP14 and other SRP polypeptides at submicromolar concentrations and kills parasites [#0]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"24434517","id":"PMC_24434517","title":"Plasmodium falciparum signal recognition particle components and anti-parasitic effect of ivermectin in blocking nucleo-cytoplasmic shuttling of SRP.","date":"2014","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/24434517","citation_count":51,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SRP14"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"17919451","id":"PMC_17919451","title":"Unraveling the components of protein translocation pathway in human malaria parasite Plasmodium falciparum.","date":"2007","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/17919451","citation_count":25,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SRP14"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34017052","id":"","title":"Structural analysis of the SRP Alu domain from Plasmodium falciparum reveals a non-canonical open conformation.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/34017052","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SRP14"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"14720308","id":"","title":"Identification and comparative analysis of components from the signal recognition particle in protozoa and fungi.","date":"2004","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/14720308","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SRP14"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6246,"output_tokens":1153,"usd":0.018017,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5991,"output_tokens":2402,"usd":0.045003,"stage2_stop_reason":"end_turn"},"total_usd":0.06302,"stage1_batch_id":"msgbatch_01SRp5hyRc82zNjddxyCCXGk","stage2_batch_id":"msgbatch_01K3BTmBazRo3pRrMvyaPMTY","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"P. falciparum SRP14 is one of six polypeptides (SRP9, SRP14, SRP19, SRP54, SRP68, SRP72) that compose the P. falciparum SRP ribonucleoprotein complex together with a 303 nt SRP RNA. GFP-tagged SRP14 expressed in transgenic parasites localizes to both nucleus and cytoplasm (nucleo-cytoplasmic shuttling), and ivermectin (an importin α/β-mediated nuclear import inhibitor) blocks nuclear import of PfSRP polypeptides including SRP14 at submicromolar concentrations, killing the parasites.\",\n      \"method\": \"Transgenic P. falciparum lines expressing SRP14-GFP chimeric proteins; fluorescence co-localization microscopy; pharmacological inhibition with ivermectin\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with GFP fusion in live parasites and functional consequence (parasite killing) via pharmacological inhibition, single lab with two orthogonal methods\",\n      \"pmids\": [\"24434517\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The P. falciparum SRP14 protein forms a heterodimer with SRP9 (PfSRP9/14) as part of the Alu domain. SAXS analysis shows the PfSRP9/14 heterodimer adopts a compact, folded globular conformation (Dmax ~7.2 nm), and the ab initio envelope accommodates the human SRP9/14 heterodimer crystal structure. PfSRP14 contains an extended internal loop L1 (residues 35–70) absent in human SRP14. The PfAlu domain (comprising PfSRP9/14 and PfAlu RNA) adopts an open Y-shaped conformation—distinct from the canonical closed conformation—and P. falciparum cytoplasmic ribosomes bind both the open PfAlu and closed human Alu domains with nanomolar affinity.\",\n      \"method\": \"NMR, SAXS, and cryo-EM structural analyses of recombinant PfSRP9/14 heterodimer and PfAlu RNA expressed in E. coli; ribosome binding affinity measurements\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal structural methods (NMR, SAXS, cryo-EM) with functional validation (ribosome binding affinity) in a single rigorous study\",\n      \"pmids\": [\"34017052\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Bioinformatic genome analysis identified SRP14 and SRP9 homologs in P. falciparum (SRP14 previously annotated as a hypothetical protein, accession PFL0160w), establishing SRP14 as a component of the P. falciparum SRP Alu domain alongside SRP9.\",\n      \"method\": \"Comparative genomic/bioinformatic analysis of protozoan genome sequences\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no direct biochemical experiment performed on the P. falciparum protein\",\n      \"pmids\": [\"14720308\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"P. falciparum SRP14 (PF3D7_1203200) forms a compact heterodimer with SRP9 as the protein component of the SRP Alu domain; unlike its human counterpart, the PfSRP9/14 heterodimer contains an extended internal loop (L1) and the intact PfAlu domain adopts an open Y-shaped conformation that is recognized with nanomolar affinity by P. falciparum ribosomes; in live parasites, SRP14 undergoes nucleo-cytoplasmic shuttling via importin α/β-dependent nuclear import, which can be blocked by ivermectin.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1203200 (SRP14) is the protein component of the Alu domain of the P. falciparum signal recognition particle, a ribonucleoprotein complex of six polypeptides (SRP9, SRP14, SRP19, SRP54, SRP68, SRP72) assembled on a 303 nt SRP RNA [#0]. SRP14 forms a compact, folded globular heterodimer with SRP9 (PfSRP9/14), which together with the PfAlu RNA constitutes the PfAlu domain; unlike its human counterpart, PfSRP14 carries an extended internal loop L1 (residues 35–70), and the intact PfAlu domain adopts an open Y-shaped conformation rather than the canonical closed form, yet is bound by P. falciparum cytoplasmic ribosomes with nanomolar affinity [#1]. In live parasites, GFP-tagged SRP14 shuttles between nucleus and cytoplasm, and its nuclear import is importin α/β-dependent and blocked by ivermectin at submicromolar concentrations, which kills the parasite [#0]. Beyond its structural role in the Alu domain, its ribosome-binding property, and its nucleo-cytoplasmic trafficking, no further mechanistic detail on PF3D7_1203200 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Before any experimental work, it was unknown whether P. falciparum even encoded an SRP Alu-domain protein; genome analysis answered this by identifying an SRP14 homolog, establishing the gene as a candidate SRP component.\",\n      \"evidence\": \"Comparative genomic/bioinformatic analysis of protozoan genomes, annotating the former hypothetical protein PFL0160w\",\n      \"pmids\": [\"14720308\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Computational prediction only; no biochemical validation of the P. falciparum protein\",\n        \"Did not establish whether the predicted protein assembles into an SRP complex or binds RNA\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"It was unknown where SRP14 resides in the parasite or whether its trafficking is druggable; live-parasite imaging placed SRP14 in a six-polypeptide SRP complex and showed importin-dependent nucleo-cytoplasmic shuttling that ivermectin blocks, linking SRP14 trafficking to parasite viability.\",\n      \"evidence\": \"Transgenic SRP14-GFP P. falciparum lines with co-localization microscopy and pharmacological ivermectin inhibition\",\n      \"pmids\": [\"24434517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ivermectin acts on general importin α/β import, so the killing effect is not proven to be SRP14-specific\",\n        \"Functional role of nuclear localization for an SRP protein remains undefined\",\n        \"Assembly stoichiometry and order within the SRP complex not resolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The structural basis of the parasite Alu domain and how it differs from the human counterpart was unknown; multi-method structural analysis showed PfSRP14 forms a globular heterodimer with SRP9, carries a unique extended L1 loop, and yields an open Y-shaped Alu domain that nonetheless binds ribosomes with nanomolar affinity.\",\n      \"evidence\": \"NMR, SAXS, and cryo-EM of recombinant PfSRP9/14 and PfAlu RNA from E. coli, with ribosome-binding affinity measurements\",\n      \"pmids\": [\"34017052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of the open Y-shaped conformation for translational arrest was not tested\",\n        \"Role of the parasite-specific L1 loop not experimentally dissected\",\n        \"Structure of SRP14 within the full six-protein SRP was not determined\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the SRP14-dependent Alu domain executes canonical elongation arrest during co-translational targeting in P. falciparum, and whether SRP14 itself is essential and druggable independent of general importin inhibition, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No functional assay directly linking SRP14 to translational arrest or protein targeting in the parasite\",\n        \"No SRP14-specific genetic knockout/knockdown phenotype reported\",\n        \"Physiological significance of nuclear localization for SRP14 unestablished\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008312\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0043022\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0042803\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005737\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0048500\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006614\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0006606\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"Signal recognition particle (SRP9/SRP14/SRP19/SRP54/SRP68/SRP72 + 303 nt SRP RNA)\",\n      \"PfSRP9/14 Alu-domain heterodimer\"\n    ],\n    \"partners\": [\n      \"SRP9\",\n      \"PfAlu RNA\",\n      \"P. falciparum cytoplasmic ribosome\",\n      \"importin α/β import machinery\"\n    ],\n    \"other_free_text\": [\n      \"PfSRP14 contains a parasite-specific extended internal loop L1 (residues 35–70) absent in human SRP14 [#1]\",\n      \"The intact PfAlu domain adopts an open Y-shaped conformation distinct from the canonical closed form yet binds ribosomes with nanomolar affinity [#1]\",\n      \"Ivermectin blocks importin α/β-dependent nuclear import of SRP14 and other SRP polypeptides at submicromolar concentrations and kills parasites [#0]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1203200","name":null,"product":"signal recognition particle subunit SRP14","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0602200","name":null,"product":"signal recognition particle subunit SRP14, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1303100","name":null,"product":"signal recognition particle subunit SRP14, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"SRP14","evaluation":null}