{"gene":"PF3D7_0702400","run_date":"2026-09-08T16:26:55","timeline":{"discoveries":[{"year":2014,"finding":"SEMP1 (PF3D7_0702400) is a Maurer's cleft (MC) membrane protein that, upon RBC invasion, is exported into the RBC cytosol, inserts into Maurer's clefts, and is partly translocated to the RBC membrane. It is a PNEP (exported without a PEXEL motif) and contains a single transmembrane domain.","method":"Live imaging, subcellular fractionation, IFA, conditional loss-of-function (conditional knockdown)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with functional consequence, multiple orthogonal methods (live imaging, fractionation, IFA, loss-of-function) in the characterizing study, independently confirmed by multiple subsequent studies","pmids":["25062022"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"SEMP1 is not essential for parasite survival, gametocytogenesis, or PfEMP1 export under standard culture conditions, as shown by conventional and conditional loss-of-function approaches.","method":"Conventional and conditional loss-of-function (knockdown/knockout)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent loss-of-function approaches with specific phenotypic readouts, single characterizing paper but multiple orthogonal methods","pmids":["25062022"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"Co-immunoprecipitation of SEMP1 identified REX1 and other membrane-associated proteins as interaction partners that co-localize with SEMP1 at Maurer's clefts.","method":"Co-immunoprecipitation (Co-IP) followed by mass spectrometry, confirmed by co-localization IFA","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP with co-localization confirmation, single lab, independently referenced in subsequent studies","pmids":["25062022"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"Transcriptome analysis showed that expression of a number of exported parasite proteins was up-regulated in SEMP1-depleted parasites, suggesting SEMP1 participates in regulating exported protein expression.","method":"Transcriptome analysis of SEMP1-depleted parasites","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — transcriptome readout from loss-of-function, single lab, indirect evidence of regulatory role","pmids":["25062022"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"SEMP1 was identified as a component of a putative PfEMP1 unloading hub at Maurer's clefts, clustering with REX1, PTP5, and PF3D7_1353100 in a protein interaction network derived from reciprocal Co-IP and mass spectrometry experiments.","method":"Co-immunoprecipitation with GFP-tagged Maurer's cleft proteins, mass spectrometry, network analysis combining published SEMP1 IP data","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP/MS with network integration across multiple bait proteins including published SEMP1 IP data, single study but multiple reciprocal IPs support the cluster","pmids":["32184257"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2023,"finding":"Proximity labeling (TurboID) from cytosolic-facing bait proteins (KAHRP and PTP4) detected biotinylation only at the N-terminus of SEMP1, indicating that its single transmembrane domain is inserted into Maurer's cleft membranes with the N-terminus exposed to the RBC cytosol.","method":"TurboID proximity labeling with site-specific biotinylated peptide quantification (PerTurboID)","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific biotinylation approach defines topology, single lab, single study with systematic controls","pmids":["37737226"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"SEMP1 was detected as a proximity-biotinylated protein in KAHRP-APEX2 experiments, indicating it resides in the local protein environment of KAHRP at Maurer's clefts during intraerythrocytic development.","method":"APEX2-based proximity biotinylation followed by label-free shotgun proteomics","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single proximity labeling experiment, indirect co-localization inference, no direct functional validation of the interaction","pmids":["38755230"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"finding":"SEMP1 phosphopeptides were more abundant following febrile heat stress (39°C), and SEMP1 was detected by FIKK10.2-TurboID proximity labeling, consistent with increased trafficking/accessibility of this Maurer's cleft protein under heat stress conditions.","method":"Phosphoproteomics and TurboID proximity labeling under heat-stress conditions","journal":"eLife","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, phosphopeptide detection infers modification but no writer/eraser identified, indirect functional inference","pmids":["42126964"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"finding":"SEMP1 levels were significantly reduced in MAHRP2 conditional knockout parasites, indicating that MAHRP2 is required to maintain normal SEMP1 abundance at Maurer's clefts.","method":"Conditional knockout of MAHRP2 followed by quantitative proteomics","journal":"Frontiers in cellular and infection microbiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — SEMP1 reduction is a secondary finding in a MAHRP2 KO study, single lab, single method (proteomics), no direct functional follow-up for SEMP1 itself","pmids":["42291314"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2017,"finding":"SEMP1 was identified among the most abundant proteins in extracellular vesicles (EVs) from a P. falciparum clinical isolate, and 13 of 14 proteins co-precipitated with SEMP1 in prior Co-IP experiments were also detected in PfEVs, linking SEMP1's MC-resident interactome to EV biogenesis.","method":"Proteomic analysis of extracellular vesicles by mass spectrometry, cross-referenced with published SEMP1 Co-IP data","journal":"Wellcome open research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proteomic detection of SEMP1 in EVs, no direct functional experiments on SEMP1 EV association, co-IP overlap is a correlative observation","pmids":["28944300"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"SEMP1 (PF3D7_0702400) is a PNEP Maurer's cleft membrane protein in P. falciparum that is exported into the RBC cytosol after invasion, inserts into Maurer's clefts via a single transmembrane domain with its N-terminus facing the RBC cytosol, and is partly translocated to the RBC membrane; it is non-essential for parasite survival or PfEMP1 export under standard conditions but participates in a MC-associated protein complex (including REX1 and a putative PfEMP1-unloading hub), its depletion up-regulates expression of other exported proteins, and its abundance depends in part on MAHRP2."},"narrative":{"mechanistic_narrative":"SEMP1 (PF3D7_0702400) is a PEXEL-negative exported protein (PNEP) of Plasmodium falciparum that, following erythrocyte invasion, is exported into the red blood cell cytosol and inserts into Maurer's cleft membranes through its single transmembrane domain, with a fraction further translocated to the RBC plasma membrane [PMID:25062022]. Site-specific proximity labeling from cytosolic-facing baits establishes that its transmembrane domain adopts a topology with the N-terminus exposed to the RBC cytosol [PMID:37737226]. At Maurer's clefts SEMP1 participates in a membrane-associated protein complex that includes REX1 and clusters with REX1, PTP5, and PF3D7_1353100 in a putative PfEMP1-unloading hub [PMID:25062022, PMID:32184257]. Despite this complex membership, SEMP1 is dispensable for parasite survival, gametocytogenesis, and PfEMP1 export under standard culture conditions, and its depletion up-regulates the expression of other exported proteins, implicating it in the regulation of the exported proteome [PMID:25062022]. Beyond its Maurer's cleft residency, complex membership, and this regulatory phenotype, no catalytic activity or direct molecular function for SEMP1 has been characterized in the available corpus.","teleology":[{"year":2014,"claim":"Establishing where SEMP1 goes and how it is trafficked was the first step in placing it within the host-cell remodeling machinery; it was shown to be a PNEP that is exported and inserts into Maurer's clefts.","evidence":"Live imaging, subcellular fractionation, IFA, and conditional loss-of-function in P. falciparum","pmids":["25062022"],"confidence":"High","gaps":["Mechanism of PNEP export and cleft insertion not defined","Signal directing partial translocation to the RBC membrane unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"Whether SEMP1 is required for the parasite's key virulence functions was tested; two independent loss-of-function approaches showed it is dispensable for survival, gametocytogenesis, and PfEMP1 export, arguing against an essential structural role.","evidence":"Conventional and conditional knockdown/knockout with phenotypic readouts in P. falciparum","pmids":["25062022"],"confidence":"High","gaps":["Possible functional redundancy with sibling exported proteins not excluded","Non-standard conditions (e.g. stress, in vivo) not tested in this study"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"To find SEMP1's molecular context, Co-IP was used to identify REX1 and other membrane-associated cleft proteins as partners, defining it as a component of a Maurer's cleft complex.","evidence":"Co-IP/mass spectrometry with co-localization IFA in P. falciparum","pmids":["25062022"],"confidence":"Medium","gaps":["Direct versus indirect binding within the complex not resolved","Stoichiometry and architecture of the complex undefined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"Transcriptome profiling of SEMP1-depleted parasites addressed whether SEMP1 has a regulatory output, showing up-regulation of multiple exported proteins and implicating it in regulating the exported proteome.","evidence":"Transcriptome analysis of SEMP1-depleted parasites in P. falciparum","pmids":["25062022"],"confidence":"Medium","gaps":["Mechanism linking SEMP1 loss to transcriptional up-regulation unknown","Whether the effect is direct or a compensatory response unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Reciprocal Co-IP/network analysis refined SEMP1's complex assignment, placing it in a putative PfEMP1 unloading hub clustered with REX1, PTP5, and PF3D7_1353100.","evidence":"Co-IP with GFP-tagged cleft baits, mass spectrometry, and network integration in P. falciparum 3D7","pmids":["32184257"],"confidence":"Medium","gaps":["SEMP1's specific contribution to PfEMP1 unloading not functionally demonstrated","Hub composition inferred from network clustering rather than direct binding"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2023,"claim":"The membrane topology of SEMP1 was resolved; site-specific proximity biotinylation from cytosolic baits marked only the N-terminus, establishing an N-terminus-in orientation for its single transmembrane domain.","evidence":"TurboID/PerTurboID with site-specific biotinylated peptide quantification in P. falciparum","pmids":["37737226"],"confidence":"Medium","gaps":["Functional consequence of this topology not established","Single-study topology assignment"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"Independent proximity labeling reinforced SEMP1's cleft residency by detecting it in the KAHRP-APEX2 local environment during intraerythrocytic development.","evidence":"APEX2 proximity biotinylation with label-free proteomics in P. falciparum","pmids":["38755230"],"confidence":"Low","gaps":["Single proximity-labeling experiment; interaction not functionally validated","Proximity to KAHRP does not establish direct binding"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"claim":"Under febrile heat stress SEMP1 phosphopeptides increased and it was detected by FIKK10.2-TurboID, hinting at stress-responsive modification and trafficking of the protein.","evidence":"Phosphoproteomics and TurboID under heat-stress conditions in P. falciparum","pmids":["42126964"],"confidence":"Low","gaps":["No kinase/phosphatase writer or eraser identified for SEMP1 sites","Functional consequence of phosphorylation not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"claim":"A MAHRP2 dependency for SEMP1 was uncovered; SEMP1 abundance dropped in MAHRP2 conditional knockouts, linking its steady-state levels to MAHRP2.","evidence":"Conditional knockout of MAHRP2 with quantitative proteomics in P. falciparum 3D7","pmids":["42291314"],"confidence":"Low","gaps":["SEMP1 reduction is a secondary finding without direct follow-up","Whether MAHRP2 acts on SEMP1 stability, trafficking, or expression unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":null,"claim":"The direct molecular function of SEMP1 within the Maurer's cleft complex — and how its dispensability reconciles with its regulatory effect on the exported proteome — remains unresolved.","evidence":"No experiment in the corpus assigns SEMP1 a catalytic or defined mechanistic role","pmids":[],"confidence":"Low","gaps":["No molecular activity or substrate identified for SEMP1","Mechanism connecting SEMP1 loss to up-regulation of exported proteins unknown","SEMP1's specific role, if any, in PfEMP1 unloading not demonstrated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Maurer's cleft membrane-associated protein complex (with REX1)","Putative PfEMP1-unloading hub (REX1, PTP5, PF3D7_1353100)"],"partners":["REX1","PTP5","PF3D7_1353100","KAHRP (PROXIMITY)","MAHRP2 (ABUNDANCE DEPENDENCY)"],"other_free_text":["PEXEL-negative exported protein (PNEP) with a single transmembrane domain, N-terminus facing the RBC cytosol","Non-essential for parasite survival, gametocytogenesis, and PfEMP1 export under standard conditions","Depletion up-regulates expression of other exported proteins","Detected among abundant proteins in P. falciparum extracellular vesicles","Phosphopeptides increased under febrile heat stress"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"25062022","id":"PMC_25062022","title":"Characterization of the small exported Plasmodium falciparum membrane protein SEMP1.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25062022","citation_count":20,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SEMP1","small exported membrane protein 1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41607793","id":"","title":"Antibody levels to variant and conserved Plasmodium falciparum antigens predict reduction in parasite burden in Malian children.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41607793","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SEMP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42291314","id":"","title":"MAHRP2 is required for tether formation and cytoadherence in Plasmodium falciparum infected red blood cells.","date":"2026","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/42291314","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SEMP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42126964","id":"","title":"Physiological febrile heat stress increases cytoadhesion through increased protein trafficking of Plasmodium falciparum surface proteins into the red blood cell.","date":"2026","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/42126964","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SEMP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37737226","id":"","title":"PerTurboID, a targeted in situ method reveals the impact of kinase deletion on its local protein environment in the cytoadhesion complex of malaria-causing parasites.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/37737226","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SEMP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38755230","id":"","title":"APEX2-based proximity proteomic analysis identifies candidate interactors for Plasmodium falciparum knob-associated histidine-rich protein in infected erythrocytes.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38755230","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SEMP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35255125","id":"","title":"Transcriptome Analysis of Plasmodium falciparum Isolates From Benin Reveals Specific Gene Expression Associated With Cerebral Malaria.","date":"2022","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/35255125","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SEMP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32620892","id":"","title":"Rapid activation of distinct members of multigene families in Plasmodium spp.","date":"2020","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/32620892","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SEMP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32184257","id":"","title":"Role of Plasmodium falciparum Protein GEXP07 in Maurer's Cleft Morphology, Knob Architecture, and P. falciparum EMP1 Trafficking.","date":"2020","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/32184257","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SEMP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28118367","id":"","title":"Characterizing Antibody Responses to Plasmodium vivax and Plasmodium falciparum Antigens in India Using Genome-Scale Protein Microarrays.","date":"2017","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/28118367","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SEMP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30995911","id":"","title":"Hospital-derived antibody profiles of malaria patients in Southwest India.","date":"2019","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/30995911","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SEMP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28252383","id":"","title":"Plasmodium falciparum parasites deploy RhopH2 into the host erythrocyte to obtain nutrients, grow and replicate.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28252383","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SEMP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28944300","id":"","title":"Proteomic analysis of extracellular vesicles from a Plasmodium falciparum Kenyan clinical isolate defines a core parasite secretome.","date":"2017","source":"Wellcome open research","url":"https://pubmed.ncbi.nlm.nih.gov/28944300","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SEMP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15197,"output_tokens":2493,"usd":0.041493,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7912,"output_tokens":3533,"usd":0.063942,"stage2_stop_reason":"end_turn"},"total_usd":0.105435,"stage1_batch_id":"msgbatch_01NE1MTa8x1hW7Lo4tAaNzY1","stage2_batch_id":"msgbatch_0141vaQdeFvbo2q39AinvXM9","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"SEMP1 (PF3D7_0702400) is a Maurer's cleft (MC) membrane protein that, upon RBC invasion, is exported into the RBC cytosol, inserts into Maurer's clefts, and is partly translocated to the RBC membrane. It is a PNEP (exported without a PEXEL motif) and contains a single transmembrane domain.\",\n      \"method\": \"Live imaging, subcellular fractionation, IFA, conditional loss-of-function (conditional knockdown)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with functional consequence, multiple orthogonal methods (live imaging, fractionation, IFA, loss-of-function) in the characterizing study, independently confirmed by multiple subsequent studies\",\n      \"pmids\": [\"25062022\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SEMP1 is not essential for parasite survival, gametocytogenesis, or PfEMP1 export under standard culture conditions, as shown by conventional and conditional loss-of-function approaches.\",\n      \"method\": \"Conventional and conditional loss-of-function (knockdown/knockout)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent loss-of-function approaches with specific phenotypic readouts, single characterizing paper but multiple orthogonal methods\",\n      \"pmids\": [\"25062022\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Co-immunoprecipitation of SEMP1 identified REX1 and other membrane-associated proteins as interaction partners that co-localize with SEMP1 at Maurer's clefts.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP) followed by mass spectrometry, confirmed by co-localization IFA\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP with co-localization confirmation, single lab, independently referenced in subsequent studies\",\n      \"pmids\": [\"25062022\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Transcriptome analysis showed that expression of a number of exported parasite proteins was up-regulated in SEMP1-depleted parasites, suggesting SEMP1 participates in regulating exported protein expression.\",\n      \"method\": \"Transcriptome analysis of SEMP1-depleted parasites\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptome readout from loss-of-function, single lab, indirect evidence of regulatory role\",\n      \"pmids\": [\"25062022\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SEMP1 was identified as a component of a putative PfEMP1 unloading hub at Maurer's clefts, clustering with REX1, PTP5, and PF3D7_1353100 in a protein interaction network derived from reciprocal Co-IP and mass spectrometry experiments.\",\n      \"method\": \"Co-immunoprecipitation with GFP-tagged Maurer's cleft proteins, mass spectrometry, network analysis combining published SEMP1 IP data\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP/MS with network integration across multiple bait proteins including published SEMP1 IP data, single study but multiple reciprocal IPs support the cluster\",\n      \"pmids\": [\"32184257\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Proximity labeling (TurboID) from cytosolic-facing bait proteins (KAHRP and PTP4) detected biotinylation only at the N-terminus of SEMP1, indicating that its single transmembrane domain is inserted into Maurer's cleft membranes with the N-terminus exposed to the RBC cytosol.\",\n      \"method\": \"TurboID proximity labeling with site-specific biotinylated peptide quantification (PerTurboID)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific biotinylation approach defines topology, single lab, single study with systematic controls\",\n      \"pmids\": [\"37737226\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEMP1 was detected as a proximity-biotinylated protein in KAHRP-APEX2 experiments, indicating it resides in the local protein environment of KAHRP at Maurer's clefts during intraerythrocytic development.\",\n      \"method\": \"APEX2-based proximity biotinylation followed by label-free shotgun proteomics\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single proximity labeling experiment, indirect co-localization inference, no direct functional validation of the interaction\",\n      \"pmids\": [\"38755230\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SEMP1 phosphopeptides were more abundant following febrile heat stress (39°C), and SEMP1 was detected by FIKK10.2-TurboID proximity labeling, consistent with increased trafficking/accessibility of this Maurer's cleft protein under heat stress conditions.\",\n      \"method\": \"Phosphoproteomics and TurboID proximity labeling under heat-stress conditions\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single study, phosphopeptide detection infers modification but no writer/eraser identified, indirect functional inference\",\n      \"pmids\": [\"42126964\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SEMP1 levels were significantly reduced in MAHRP2 conditional knockout parasites, indicating that MAHRP2 is required to maintain normal SEMP1 abundance at Maurer's clefts.\",\n      \"method\": \"Conditional knockout of MAHRP2 followed by quantitative proteomics\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — SEMP1 reduction is a secondary finding in a MAHRP2 KO study, single lab, single method (proteomics), no direct functional follow-up for SEMP1 itself\",\n      \"pmids\": [\"42291314\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SEMP1 was identified among the most abundant proteins in extracellular vesicles (EVs) from a P. falciparum clinical isolate, and 13 of 14 proteins co-precipitated with SEMP1 in prior Co-IP experiments were also detected in PfEVs, linking SEMP1's MC-resident interactome to EV biogenesis.\",\n      \"method\": \"Proteomic analysis of extracellular vesicles by mass spectrometry, cross-referenced with published SEMP1 Co-IP data\",\n      \"journal\": \"Wellcome open research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proteomic detection of SEMP1 in EVs, no direct functional experiments on SEMP1 EV association, co-IP overlap is a correlative observation\",\n      \"pmids\": [\"28944300\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"SEMP1 (PF3D7_0702400) is a PNEP Maurer's cleft membrane protein in P. falciparum that is exported into the RBC cytosol after invasion, inserts into Maurer's clefts via a single transmembrane domain with its N-terminus facing the RBC cytosol, and is partly translocated to the RBC membrane; it is non-essential for parasite survival or PfEMP1 export under standard conditions but participates in a MC-associated protein complex (including REX1 and a putative PfEMP1-unloading hub), its depletion up-regulates expression of other exported proteins, and its abundance depends in part on MAHRP2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEMP1 (PF3D7_0702400) is a PEXEL-negative exported protein (PNEP) of Plasmodium falciparum that, following erythrocyte invasion, is exported into the red blood cell cytosol and inserts into Maurer's cleft membranes through its single transmembrane domain, with a fraction further translocated to the RBC plasma membrane [#0]. Site-specific proximity labeling from cytosolic-facing baits establishes that its transmembrane domain adopts a topology with the N-terminus exposed to the RBC cytosol [#5]. At Maurer's clefts SEMP1 participates in a membrane-associated protein complex that includes REX1 and clusters with REX1, PTP5, and PF3D7_1353100 in a putative PfEMP1-unloading hub [#2, #4]. Despite this complex membership, SEMP1 is dispensable for parasite survival, gametocytogenesis, and PfEMP1 export under standard culture conditions, and its depletion up-regulates the expression of other exported proteins, implicating it in the regulation of the exported proteome [#1, #3]. Beyond its Maurer's cleft residency, complex membership, and this regulatory phenotype, no catalytic activity or direct molecular function for SEMP1 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing where SEMP1 goes and how it is trafficked was the first step in placing it within the host-cell remodeling machinery; it was shown to be a PNEP that is exported and inserts into Maurer's clefts.\",\n      \"evidence\": \"Live imaging, subcellular fractionation, IFA, and conditional loss-of-function in P. falciparum\",\n      \"pmids\": [\"25062022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of PNEP export and cleft insertion not defined\",\n        \"Signal directing partial translocation to the RBC membrane unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Whether SEMP1 is required for the parasite's key virulence functions was tested; two independent loss-of-function approaches showed it is dispensable for survival, gametocytogenesis, and PfEMP1 export, arguing against an essential structural role.\",\n      \"evidence\": \"Conventional and conditional knockdown/knockout with phenotypic readouts in P. falciparum\",\n      \"pmids\": [\"25062022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Possible functional redundancy with sibling exported proteins not excluded\",\n        \"Non-standard conditions (e.g. stress, in vivo) not tested in this study\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"To find SEMP1's molecular context, Co-IP was used to identify REX1 and other membrane-associated cleft proteins as partners, defining it as a component of a Maurer's cleft complex.\",\n      \"evidence\": \"Co-IP/mass spectrometry with co-localization IFA in P. falciparum\",\n      \"pmids\": [\"25062022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct versus indirect binding within the complex not resolved\",\n        \"Stoichiometry and architecture of the complex undefined\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Transcriptome profiling of SEMP1-depleted parasites addressed whether SEMP1 has a regulatory output, showing up-regulation of multiple exported proteins and implicating it in regulating the exported proteome.\",\n      \"evidence\": \"Transcriptome analysis of SEMP1-depleted parasites in P. falciparum\",\n      \"pmids\": [\"25062022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking SEMP1 loss to transcriptional up-regulation unknown\",\n        \"Whether the effect is direct or a compensatory response unresolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reciprocal Co-IP/network analysis refined SEMP1's complex assignment, placing it in a putative PfEMP1 unloading hub clustered with REX1, PTP5, and PF3D7_1353100.\",\n      \"evidence\": \"Co-IP with GFP-tagged cleft baits, mass spectrometry, and network integration in P. falciparum 3D7\",\n      \"pmids\": [\"32184257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"SEMP1's specific contribution to PfEMP1 unloading not functionally demonstrated\",\n        \"Hub composition inferred from network clustering rather than direct binding\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The membrane topology of SEMP1 was resolved; site-specific proximity biotinylation from cytosolic baits marked only the N-terminus, establishing an N-terminus-in orientation for its single transmembrane domain.\",\n      \"evidence\": \"TurboID/PerTurboID with site-specific biotinylated peptide quantification in P. falciparum\",\n      \"pmids\": [\"37737226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of this topology not established\",\n        \"Single-study topology assignment\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Independent proximity labeling reinforced SEMP1's cleft residency by detecting it in the KAHRP-APEX2 local environment during intraerythrocytic development.\",\n      \"evidence\": \"APEX2 proximity biotinylation with label-free proteomics in P. falciparum\",\n      \"pmids\": [\"38755230\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single proximity-labeling experiment; interaction not functionally validated\",\n        \"Proximity to KAHRP does not establish direct binding\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Under febrile heat stress SEMP1 phosphopeptides increased and it was detected by FIKK10.2-TurboID, hinting at stress-responsive modification and trafficking of the protein.\",\n      \"evidence\": \"Phosphoproteomics and TurboID under heat-stress conditions in P. falciparum\",\n      \"pmids\": [\"42126964\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No kinase/phosphatase writer or eraser identified for SEMP1 sites\",\n        \"Functional consequence of phosphorylation not tested\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A MAHRP2 dependency for SEMP1 was uncovered; SEMP1 abundance dropped in MAHRP2 conditional knockouts, linking its steady-state levels to MAHRP2.\",\n      \"evidence\": \"Conditional knockout of MAHRP2 with quantitative proteomics in P. falciparum 3D7\",\n      \"pmids\": [\"42291314\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"SEMP1 reduction is a secondary finding without direct follow-up\",\n        \"Whether MAHRP2 acts on SEMP1 stability, trafficking, or expression unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular function of SEMP1 within the Maurer's cleft complex — and how its dispensability reconciles with its regulatory effect on the exported proteome — remains unresolved.\",\n      \"evidence\": \"No experiment in the corpus assigns SEMP1 a catalytic or defined mechanistic role\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No molecular activity or substrate identified for SEMP1\",\n        \"Mechanism connecting SEMP1 loss to up-regulation of exported proteins unknown\",\n        \"SEMP1's specific role, if any, in PfEMP1 unloading not demonstrated\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0020036\", \"supporting_discovery_ids\": [0, 2, 4, 5, 6]},\n      {\"term_id\": \"GO:0016020\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0046718\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"Maurer's cleft membrane-associated protein complex (with REX1)\",\n      \"Putative PfEMP1-unloading hub (REX1, PTP5, PF3D7_1353100)\"\n    ],\n    \"partners\": [\n      \"REX1\",\n      \"PTP5\",\n      \"PF3D7_1353100\",\n      \"KAHRP (proximity)\",\n      \"MAHRP2 (abundance dependency)\"\n    ],\n    \"other_free_text\": [\n      \"PEXEL-negative exported protein (PNEP) with a single transmembrane domain, N-terminus facing the RBC cytosol\",\n      \"Non-essential for parasite survival, gametocytogenesis, and PfEMP1 export under standard conditions\",\n      \"Depletion up-regulates expression of other exported proteins\",\n      \"Detected among abundant proteins in P. falciparum extracellular vesicles\",\n      \"Phosphopeptides increased under febrile heat stress\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0702400","name":null,"product":"small exported membrane protein 1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0100600","name":null,"product":"small exported membrane protein 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"SEMP1","evaluation":null}