Reticulocyte-binding protein homolog 5 (PfRH5) is a small, secreted blood-stage adhesin of the human malaria parasite Plasmodium falciparum and the only essential member of the reticulocyte-binding-like homolog (PfRh) family. Unlike the other family members it is short and lacks both a transmembrane segment and a GPI anchor, so after synthesis in schizonts it is stored in the lumen of the rhoptries, the apical secretory organelles of the merozoite, and is discharged onto the merozoite surface at the moment of invasion. There it is held by the GPI-anchored surface protein P113, which binds its N-terminal region, and assembles with the GPI-anchored CyRPA and the EGF-domain protein PfRipr into a structurally defined trimeric invasion complex. Through its kite-shaped C-terminal domain RH5 binds basigin (BSG/CD147, the Ok blood group antigen) on the erythrocyte surface; this receptor-ligand pair is required for invasion by every parasite strain examined, and the affinity of RH5 for basigin orthologues tracks the host range of the Laverania parasites, making it a determinant of P. falciparum's restriction to humans. Receptor engagement is not merely an anchor: it triggers a calcium signal inside the erythrocyte and remodelling of the host cytoskeleton, and the complex inserts into the host membrane, after which the merozoite attaches irreversibly, forms the moving junction and enters the cell. Parasites depleted of RH5 still contact erythrocytes but cannot commit to invasion.
Definition: The ring-shaped, electron-dense zone of contact formed between the plasma membrane of an invading apicomplexan zoite and the host cell membrane, containing the parasite surface protein AMA1 and the rhoptry neck protein complex, and through which the parasite moves into a nascent parasitophorous vacuole. Also called the tight junction.
Justification: GO has microneme, rhoptry and apical complex for apicomplexan structures, but no term for the moving (tight) junction, the parasite-host structure to which RH5 is experimentally localised during erythrocyte invasion. The only existing term carrying the name, GO:0005923 bicellular tight junction, is a metazoan epithelial sealing structure and applies here only by word match. The same term is proposed in the PLAF7 AMA1 review, where AMA1 is a defining component of the junction.
Parent term: cell junction
Supporting Evidence:
Definition: A protein-containing complex, found at the apical surface of an apicomplexan merozoite during invasion of a host erythrocyte, consisting of the reticulocyte-binding protein homolog RH5, the cysteine-rich protective antigen CyRPA and the RH5-interacting protein Ripr. The complex binds the host erythrocyte receptor basigin and inserts into the host membrane, and is required for irreversible attachment and entry.
Justification: GOA records RH5's membership of this complex only as the root term GO:0032991 protein-containing complex, which conveys nothing. The complex has defined, reproducible composition and a cryo-EM structure, is shared by at least three annotated gene products (RH5, CyRPA, PfRipr) that each need a complex term, and is the object of a major vaccine effort, so a dedicated cellular component term is warranted.
Parent term: protein-containing complex
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:21909261 An EGF-like protein forms a complex with PfRh5 and is requir... | REMOVE | Summary: RH5 forms a stable, salt-resistant complex with PfRipr (PF3D7_0323400) in merozoites. Reason: The interaction itself is real, specific and well documented - this is not a claim that the binding did not happen. The problem is the term: GO:0005515 protein binding conveys no molecular function, and because the partner is a parasite protein rather than a host receptor, there is no informative child term to refine it to (unlike the basigin rows, which are MODIFYed to GO:0046789). The content of this row is RH5's membership of the RH5-CyRPA-Ripr invasion complex, which is captured by the proposed new complex term given in proposed_new_terms (and by the GO:0032991 row MODIFYed to it) and by the complex assembly described in core_functions. Removing the bare protein-binding row therefore loses no information. Supporting Evidence: PMID:21909261 The PfRh5/PfRipr complex was stably purified by ion-exchange chromatography and 350 mM NaCl in the elution buffer did not disrupt their association, suggesting the tight interaction of two proteins. PMID:21909261 The PfRipr protein localises to the apical end of the merozoites in micronemes whilst PfRh5 is contained within rhoptries and both are released during invasion when they form a complex that is shed into the culture supernatant. |
| GO:0005515 protein binding | IPI PMID:21909261 An EGF-like protein forms a complex with PfRh5 and is requir... | REMOVE | Summary: RH5 interacts directly with PfRipr; the two are co-purified as a tight complex. Reason: The interaction itself is real, specific and well documented - this is not a claim that the binding did not happen. The problem is the term: GO:0005515 protein binding conveys no molecular function, and because the partner is a parasite protein rather than a host receptor, there is no informative child term to refine it to (unlike the basigin rows, which are MODIFYed to GO:0046789). The content of this row is RH5's membership of the RH5-CyRPA-Ripr invasion complex, which is captured by the proposed new complex term given in proposed_new_terms (and by the GO:0032991 row MODIFYed to it) and by the complex assembly described in core_functions. Removing the bare protein-binding row therefore loses no information. Supporting Evidence: PMID:21909261 The PfRh5/PfRipr complex was stably purified by ion-exchange chromatography and 350 mM NaCl in the elution buffer did not disrupt their association, suggesting the tight interaction of two proteins. |
| GO:0005515 protein binding | IPI PMID:24297912 RH5-Basigin interaction plays a major role in the host tropi... | MODIFY | Summary: RH5 binds chimpanzee basigin weakly in a cross-species comparison used to explain the host restriction of P. falciparum. Reason: A real, specific binding measurement, but 'protein binding' is uninformative and the partner is a host cell-surface receptor orthologue, so the host-specific child term is the right level. The chimpanzee BSG row records a comparative affinity measurement establishing tropism; it does not assert that RH5 functions inside chimpanzees. Proposed replacements: host cell surface receptor binding Supporting Evidence: PMID:24297912 We next investigated the contribution of the recently discovered Reticulocyte-binding protein Homolog 5 (RH5)-Basigin (BSG) interaction in host-species selectivity and found that P. falciparum RH5 bound chimpanzee BSG with a significantly lower affinity than human BSG and did not bind gorilla BSG, mirroring the known host tropism of P. falciparum. |
| GO:0005515 protein binding | IPI PMID:24297912 RH5-Basigin interaction plays a major role in the host tropi... | MODIFY | Summary: RH5 binds human basigin isoform 2, the erythrocyte form of the receptor. Reason: Correct but uninformative at the 'protein binding' level; the partner is the host erythrocyte receptor, so GO:0046789 host cell surface receptor binding captures the same interaction informatively. Proposed replacements: host cell surface receptor binding Supporting Evidence: PMID:24297912 We next investigated the contribution of the recently discovered Reticulocyte-binding protein Homolog 5 (RH5)-Basigin (BSG) interaction in host-species selectivity and found that P. falciparum RH5 bound chimpanzee BSG with a significantly lower affinity than human BSG and did not bind gorilla BSG, mirroring the known host tropism of P. falciparum. PMID:22080952 By systematically screening a library of erythrocyte proteins, we have found that the Ok blood group antigen, basigin, is a receptor for PfRh5, a parasite ligand that is essential for blood stage growth. |
| GO:0005515 protein binding | IPI PMID:25296023 Crystal structure of PfRh5, an essential P. falciparum ligan... | MODIFY | Summary: Crystallographic and biochemical characterisation of RH5 bound to human basigin. Reason: The interaction is with a host cell-surface receptor, so the generic term should be refined to GO:0046789, which the gene already carries from PMID:22080952. Proposed replacements: host cell surface receptor binding Supporting Evidence: PMID:25296023 PfRh5 binds the host receptor basigin. PMID:25296023 In this study, we have determined the crystal structure of PfRh5 using diffraction data to 2.18 Γ
resolution. |
| GO:0005515 protein binding | IPI PMID:25583518 Multiprotein complex between the GPI-anchored CyRPA with PfR... | REMOVE | Summary: RH5 interacts with the GPI-anchored CyRPA, which tethers the RH5/PfRipr/CyRPA complex at the merozoite surface. Reason: The interaction itself is real, specific and well documented - this is not a claim that the binding did not happen. The problem is the term: GO:0005515 protein binding conveys no molecular function, and because the partner is a parasite protein rather than a host receptor, there is no informative child term to refine it to (unlike the basigin rows, which are MODIFYed to GO:0046789). The content of this row is RH5's membership of the RH5-CyRPA-Ripr invasion complex, which is captured by the proposed new complex term given in proposed_new_terms (and by the GO:0032991 row MODIFYed to it) and by the complex assembly described in core_functions. Removing the bare protein-binding row therefore loses no information. Supporting Evidence: PMID:25583518 Here we have identified a conserved GPI-linked parasite protein, Cysteine-rich protective antigen (CyRPA) as an interacting partner of PfRH5-PfRipr that tethers the PfRH5/PfRipr/CyRPA multiprotein complex on the merozoite surface. |
| GO:0005515 protein binding | IPI PMID:27374406 Essential Role of the PfRh5/PfRipr/CyRPA Complex during Plas... | REMOVE | Summary: RH5 is in complex with PfRipr and CyRPA, which colocalise with it at the merozoite-erythrocyte junction. Reason: The interaction itself is real, specific and well documented - this is not a claim that the binding did not happen. The problem is the term: GO:0005515 protein binding conveys no molecular function, and because the partner is a parasite protein rather than a host receptor, there is no informative child term to refine it to (unlike the basigin rows, which are MODIFYed to GO:0046789). The content of this row is RH5's membership of the RH5-CyRPA-Ripr invasion complex, which is captured by the proposed new complex term given in proposed_new_terms (and by the GO:0032991 row MODIFYed to it) and by the complex assembly described in core_functions. Removing the bare protein-binding row therefore loses no information. Supporting Evidence: PMID:27374406 P. falciparum reticulocyte binding homolog 5 (PfRh5) forms a complex with the PfRh5-interacting protein (PfRipr) and Cysteine-rich protective antigen (CyRPA) and binds erythrocytes via the host receptor basigin. PMID:27374406 Super-resolution microscopy revealed that PfRipr, CyRPA, and PfRh5 colocalize at the junction between merozoites and erythrocytes during invasion. |
| GO:0005515 protein binding | IPI PMID:28096331 One-step design of a stable variant of the malaria invasion ... | MODIFY | Summary: Engineered stabilised RH5 variants retain binding to human basigin. Reason: Host receptor binding; refine the generic term to GO:0046789 rather than leaving an uninformative 'protein binding' row. Proposed replacements: host cell surface receptor binding Supporting Evidence: PMID:28096331 PfRH5 is released onto the surface of infective Plasmodium falciparum merozoites, binding to human basigin in an interaction that is essential for erythrocyte invasion ( 4 β 7 ). |
| GO:0005515 protein binding | IPI PMID:28186186 P113 is a merozoite surface protein that binds the N terminu... | REMOVE | Summary: Binding interdependencies of the RH5 complex components (PfRipr, CyRPA) measured with recombinant proteins. Reason: The interaction itself is real, specific and well documented - this is not a claim that the binding did not happen. The problem is the term: GO:0005515 protein binding conveys no molecular function, and because the partner is a parasite protein rather than a host receptor, there is no informative child term to refine it to (unlike the basigin rows, which are MODIFYed to GO:0046789). The content of this row is RH5's membership of the RH5-CyRPA-Ripr invasion complex, which is captured by the proposed new complex term given in proposed_new_terms (and by the GO:0032991 row MODIFYed to it) and by the complex assembly described in core_functions. Removing the bare protein-binding row therefore loses no information. Supporting Evidence: PMID:28186186 we establish the binding interdependencies of all the other known RH5 complex components and conclude that the RH5Nt-P113 interaction provides a releasable mechanism for anchoring RH5 to the merozoite surface. |
| GO:0005515 protein binding | IPI PMID:28186186 P113 is a merozoite surface protein that binds the N terminu... | MODIFY | Summary: RH5 binds human basigin; the C-terminal region, not the P113-binding N terminus, carries the basigin site. Reason: Host receptor binding; GO:0046789 is the informative child term for this interaction. Proposed replacements: host cell surface receptor binding Supporting Evidence: PMID:28186186 The role of RH5 as an invasion ligand was established by the identification of basigin as its erythrocyte receptor, and the demonstration that the RH5-basigin interaction was both essential and universally required for invasion9. |
| GO:0005515 protein binding | IPI PMID:28186186 P113 is a merozoite surface protein that binds the N terminu... | REMOVE | Summary: Direct RH5-CyRPA interaction within the invasion complex. Reason: The interaction itself is real, specific and well documented - this is not a claim that the binding did not happen. The problem is the term: GO:0005515 protein binding conveys no molecular function, and because the partner is a parasite protein rather than a host receptor, there is no informative child term to refine it to (unlike the basigin rows, which are MODIFYed to GO:0046789). The content of this row is RH5's membership of the RH5-CyRPA-Ripr invasion complex, which is captured by the proposed new complex term given in proposed_new_terms (and by the GO:0032991 row MODIFYed to it) and by the complex assembly described in core_functions. Removing the bare protein-binding row therefore loses no information. Supporting Evidence: PMID:28186186 we establish the binding interdependencies of all the other known RH5 complex components and conclude that the RH5Nt-P113 interaction provides a releasable mechanism for anchoring RH5 to the merozoite surface. PMID:28195530 We show CyRPA interacts directly with PfRh5. |
| GO:0005515 protein binding | IPI PMID:28186186 P113 is a merozoite surface protein that binds the N terminu... | REMOVE | Summary: P113 binds the N terminus of unprocessed RH5 and provides a releasable tether holding RH5 on the merozoite surface. Reason: The interaction itself is real, specific and well documented - this is not a claim that the binding did not happen. The problem is the term: GO:0005515 protein binding conveys no molecular function, and because the partner is a parasite protein rather than a host receptor, there is no informative child term to refine it to (unlike the basigin rows, which are MODIFYed to GO:0046789). The content of this row is RH5's membership of the RH5-CyRPA-Ripr invasion complex, which is captured by the proposed new complex term given in proposed_new_terms (and by the GO:0032991 row MODIFYed to it) and by the complex assembly described in core_functions. Removing the bare protein-binding row therefore loses no information. Supporting Evidence: PMID:28186186 Here we use a sensitive assay that detects interactions between recombinant proteins to show that the glycosylphosphatidylinositol (GPI)-linked protein P113 interacts directly with the N terminus of unprocessed RH5, providing a mechanism by which the RH5 invasion complex is tethered to the merozoite surface. PMID:28186186 we establish the binding interdependencies of all the other known RH5 complex components and conclude that the RH5Nt-P113 interaction provides a releasable mechanism for anchoring RH5 to the merozoite surface. |
| GO:0005515 protein binding | IPI PMID:28195530 Structural basis for inhibition of erythrocyte invasion by a... | REMOVE | Summary: CyRPA interacts directly with RH5; an invasion-inhibitory anti-CyRPA antibody blocks this contact. Reason: The interaction itself is real, specific and well documented - this is not a claim that the binding did not happen. The problem is the term: GO:0005515 protein binding conveys no molecular function, and because the partner is a parasite protein rather than a host receptor, there is no informative child term to refine it to (unlike the basigin rows, which are MODIFYed to GO:0046789). The content of this row is RH5's membership of the RH5-CyRPA-Ripr invasion complex, which is captured by the proposed new complex term given in proposed_new_terms (and by the GO:0032991 row MODIFYed to it) and by the complex assembly described in core_functions. Removing the bare protein-binding row therefore loses no information. Supporting Evidence: PMID:28195530 We show CyRPA interacts directly with PfRh5. PMID:28195530 An invasion inhibitory monoclonal antibody to CyRPA blocks binding of CyRPA to PfRh5 and complex formation thus illuminating the molecular mechanism for inhibition of parasite growth. |
| GO:0005515 protein binding | IPI PMID:30542156 Structure of Plasmodium falciparum Rh5-CyRPA-Ripr invasion c... | REMOVE | Summary: Cryo-EM structure of the Rh5-CyRPA-Ripr complex defines the Rh5-CyRPA and CyRPA-Ripr contacts. Reason: The interaction itself is real, specific and well documented - this is not a claim that the binding did not happen. The problem is the term: GO:0005515 protein binding conveys no molecular function, and because the partner is a parasite protein rather than a host receptor, there is no informative child term to refine it to (unlike the basigin rows, which are MODIFYed to GO:0046789). The content of this row is RH5's membership of the RH5-CyRPA-Ripr invasion complex, which is captured by the proposed new complex term given in proposed_new_terms (and by the GO:0032991 row MODIFYed to it) and by the complex assembly described in core_functions. Removing the bare protein-binding row therefore loses no information. Supporting Evidence: PMID:30542156 Our structure identifies blades 4-6 of the Ξ²-propeller of CyRPA as contact sites for Rh5 and Ripr. PMID:30542156 Here we show that the Rh5-CyRPA-Ripr complex binds the erythrocyte cell line JK-1 significantly better than does Rh5 alone, and that this binding occurs through the insertion of Rh5 and Ripr into host membranes as a complex with high molecular weight. |
| GO:0005515 protein binding | IPI PMID:30542156 Structure of Plasmodium falciparum Rh5-CyRPA-Ripr invasion c... | MODIFY | Summary: The Rh5-CyRPA-Ripr complex engages the erythrocyte receptor basigin, with Rh5 providing the receptor-binding contact. Reason: Host receptor binding; refine to GO:0046789. Proposed replacements: host cell surface receptor binding Supporting Evidence: PMID:30542156 These interactions include the binding of the Rh5-CyRPA-Ripr complex with the erythrocyte receptor basigin1,2, which is an essential step for entry into human erythrocytes. |
| GO:0005515 protein binding | IPI PMID:30542156 Structure of Plasmodium falciparum Rh5-CyRPA-Ripr invasion c... | MODIFY | Summary: Binding to the erythrocyte isoform of basigin within the Rh5-CyRPA-Ripr complex. Reason: Host receptor binding; refine to GO:0046789. Proposed replacements: host cell surface receptor binding Supporting Evidence: PMID:30542156 These interactions include the binding of the Rh5-CyRPA-Ripr complex with the erythrocyte receptor basigin1,2, which is an essential step for entry into human erythrocytes. |
| GO:0005576 extracellular region | EXP PMID:19000690 Reticulocyte-binding protein homologue 5 - an essential adhe... | ACCEPT | Summary: RH5 is a secreted protein: it has a signal peptide, no transmembrane domain and no GPI anchor, and is released from the merozoite at invasion. Reason: Secretion is integral to how RH5 works: it is discharged from the rhoptries onto the merozoite surface and into the interface with the erythrocyte. The term is correct and is the parasite-side counterpart of the host-side GO:0043655 rows. Supporting Evidence: PMID:19000690 This protein is an atypical PfRh family member, being much smaller than others and lacking a transmembrane and cytosolic region at the C-terminus. PMID:19000690 PfRh5 localises to the rhoptries in merozoites and follows the tight junction during the process of erythrocyte invasion. |
| GO:0005576 extracellular region | EXP PMID:21909261 An EGF-like protein forms a complex with PfRh5 and is requir... | ACCEPT | Summary: RH5 is released during invasion and shed into the culture supernatant together with PfRipr. Reason: Direct demonstration of the secreted pool of RH5. Supporting Evidence: PMID:21909261 The PfRipr protein localises to the apical end of the merozoites in micronemes whilst PfRh5 is contained within rhoptries and both are released during invasion when they form a complex that is shed into the culture supernatant. |
| GO:0005576 extracellular region | EXP PMID:25583518 Multiprotein complex between the GPI-anchored CyRPA with PfR... | ACCEPT | Summary: RH5 lacks a transmembrane domain and GPI anchor and is held at the merozoite surface only through its partners, consistent with a secreted protein. Reason: Consistent with the UniProt subcellular location and with the tethering mechanism described for the complex. Supporting Evidence: PMID:25583518 Here we have identified a conserved GPI-linked parasite protein, Cysteine-rich protective antigen (CyRPA) as an interacting partner of PfRH5-PfRipr that tethers the PfRH5/PfRipr/CyRPA multiprotein complex on the merozoite surface. |
| GO:0005576 extracellular region | EXP PMID:28409866 P. falciparum RH5-Basigin interaction induces changes in the... | ACCEPT | Summary: Secreted RH5 engages basigin on the erythrocyte surface from outside the host cell. Reason: The functional interaction demonstrated here takes place extracellularly, supporting the secreted location. Supporting Evidence: PMID:28409866 We show that RH5-Basigin interaction on its own triggers a Ca2+ signal in the RBC resulting in changes in RBC cytoskeletal proteins phosphorylation and overall alterations in RBC cytoskeleton architecture. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic mapping of the UniProt 'Secreted' subcellular location to GO:0005576. Reason: The UniProt location it maps from is itself experimentally supported for RH5, so the electronic row reinforces the EXP rows rather than over-reaching. Supporting Evidence: PMID:21909261 The PfRipr protein localises to the apical end of the merozoites in micronemes whilst PfRh5 is contained within rhoptries and both are released during invasion when they form a complex that is shed into the culture supernatant. |
| GO:0005923 bicellular tight junction | IDA PMID:19000690 Reticulocyte-binding protein homologue 5 - an essential adhe... | MODIFY | Summary: Annotation derived from the observation that RH5 'follows the tight junction' during erythrocyte invasion. Reason: GO:0005923 bicellular tight junction is defined as 'An occluding cell-cell junction that is composed of a branching network of sealing strands that completely encircles the apical end of each cell in an epithelial sheet' - a metazoan epithelial structure built from claudin/occludin strands. The apicomplexan structure RH5 tracks is the moving junction between merozoite and erythrocyte, a transient parasite-host ring that shares only the informal name 'tight junction' used in the invasion literature; the same complex is described as forming the 'moving junction' in PMID:28186186. This is an animal-specific term imported on a word match, and it asserts an epithelial sealing structure that does not exist in this system. The underlying observation is nevertheless a genuine IDA localisation of RH5 to that parasite-host structure, so rather than discarding it the row is re-termed to the proposed 'moving junction' term (see proposed_new_terms; the same term is proposed in the PLAF7 AMA1 review). Until that term exists, RH5's location at the interface remains partially captured by GO:0020002 host cell plasma membrane and GO:0043655 host extracellular region. Proposed replacements: moving junction Supporting Evidence: PMID:19000690 PfRh5 localises to the rhoptries in merozoites and follows the tight junction during the process of erythrocyte invasion. PMID:28186186 Live imaging in the presence of fluorescent calcium-sensitive dyes and RH5-basigin interaction antagonists revealed that merozoites could still adhere and deform erythrocytes leading to the conclusion that the RH5-basigin interaction was necessary for, and directly preceded, rhoptry release just before the formation of the moving junction4. |
| GO:0008201 heparin binding | IDA PMID:24212193 Analyses of interactions between heparin and the apical surf... | KEEP AS NON CORE | Summary: Native PfRH5 binds heparin with very high affinity in heparin-affinity chromatography of parasite extracts, and heparin disrupts its erythrocyte binding. Reason: The binding is directly demonstrated and the term is correct, but heparin/heparan sulfate is not a component of the mature erythrocyte surface, and the physiological receptor is basigin. The heparin affinity most likely reports the same basic, ligand-binding surface that engages the erythrocyte, and heparin acts here as an experimental invasion inhibitor rather than a biological partner. Retained as a genuine but peripheral biochemical property. Supporting Evidence: PMID:24212193 Two of these proteins, BAEBL and PfRH5, were eluted incompletely by 10 mg/mL heparin, suggesting that they have an extremely high affinity for heparin. PMID:24212193 Erythrocyte binding of some parasite ligands, including full-length MSP1, the C-terminal 42-kDa fragment of MSP1 (MSP1β42), and PfRH5 is disrupted by heparin101123, raising the possibility that heparin-induced inhibition of the binding of multiple ligands results in invasion inhibition. |
| GO:0020002 host cell plasma membrane | EXP PMID:25583518 Multiprotein complex between the GPI-anchored CyRPA with PfR... | ACCEPT | Summary: RH5 is presented on the merozoite surface in a complex that engages the erythrocyte membrane during invasion. Reason: RH5 is delivered onto the erythrocyte surface and, within the Rh5-CyRPA-Ripr complex, inserts into the host membrane at the merozoite-erythrocyte interface. The host-side location term is used correctly here (the parasite protein is located in a host compartment), and is distinct from the parasite-side secreted pool recorded by GO:0005576. Supporting Evidence: PMID:25583518 Here we have identified a conserved GPI-linked parasite protein, Cysteine-rich protective antigen (CyRPA) as an interacting partner of PfRH5-PfRipr that tethers the PfRH5/PfRipr/CyRPA multiprotein complex on the merozoite surface. PMID:28195038 While merozoites deficient in PfCyRPA or PfRH5 can still bind to erythrocytes, they do not attach irreversibly and cannot invade the host cells (Volz et al., 2016). |
| GO:0020002 host cell plasma membrane | EXP PMID:27374406 Essential Role of the PfRh5/PfRipr/CyRPA Complex during Plas... | ACCEPT | Summary: RH5 colocalises with CyRPA and PfRipr at the junction with the erythrocyte membrane during invasion. Reason: RH5 is delivered onto the erythrocyte surface and, within the Rh5-CyRPA-Ripr complex, inserts into the host membrane at the merozoite-erythrocyte interface. The host-side location term is used correctly here (the parasite protein is located in a host compartment), and is distinct from the parasite-side secreted pool recorded by GO:0005576. Supporting Evidence: PMID:27374406 Super-resolution microscopy revealed that PfRipr, CyRPA, and PfRh5 colocalize at the junction between merozoites and erythrocytes during invasion. PMID:27374406 PfRipr, CyRPA, and PfRipr/CyRPA/PfRh5-basigin complex is required for triggering the Ca(2+) release and establishing the tight junction. |
| GO:0020002 host cell plasma membrane | EXP PMID:30542156 Structure of Plasmodium falciparum Rh5-CyRPA-Ripr invasion c... | ACCEPT | Summary: Rh5 and Ripr insert into the host erythrocyte membrane as a high-molecular-weight complex. Reason: RH5 is delivered onto the erythrocyte surface and, within the Rh5-CyRPA-Ripr complex, inserts into the host membrane at the merozoite-erythrocyte interface. The host-side location term is used correctly here (the parasite protein is located in a host compartment), and is distinct from the parasite-side secreted pool recorded by GO:0005576. Supporting Evidence: PMID:30542156 Here we show that the Rh5-CyRPA-Ripr complex binds the erythrocyte cell line JK-1 significantly better than does Rh5 alone, and that this binding occurs through the insertion of Rh5 and Ripr into host membranes as a complex with high molecular weight. PMID:30542156 These interactions include the binding of the Rh5-CyRPA-Ripr complex with the erythrocyte receptor basigin1,2, which is an essential step for entry into human erythrocytes. |
| GO:0020002 host cell plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic mapping of the UniProt host cell membrane location to GO:0020002. Reason: Reinforces the experimental host-membrane rows; the UniProt location it maps from is itself EXP-supported for RH5. Supporting Evidence: PMID:30542156 Here we show that the Rh5-CyRPA-Ripr complex binds the erythrocyte cell line JK-1 significantly better than does Rh5 alone, and that this binding occurs through the insertion of Rh5 and Ripr into host membranes as a complex with high molecular weight. |
| GO:0020008 rhoptry | IDA PMID:18827878 PfRH5: a novel reticulocyte-binding family homolog of plasmo... | ACCEPT | Summary: Immunofluorescence against a rhoptry marker and immuno-electron microscopy place RH5 in the rhoptries of developing merozoites. Reason: The rhoptry is a genuine apicomplexan secretory organelle and this is the pre-secretion storage site of RH5, a core part of how the protein reaches its site of action. Supporting Evidence: PMID:18827878 Thus, like the other RH ligands, PfRH5 is localized within the rhoptries, strongly suggesting a role in merozoite invasion. |
| GO:0020008 rhoptry | IDA PMID:19000690 Reticulocyte-binding protein homologue 5 - an essential adhe... | ACCEPT | Summary: RH5 localises to the rhoptries in merozoites and is released at invasion. Reason: Independent confirmation of the rhoptry localisation; consistent with the immuno-EM in PMID:18827878. Supporting Evidence: PMID:19000690 PfRh5 localises to the rhoptries in merozoites and follows the tight junction during the process of erythrocyte invasion. |
| GO:0032991 protein-containing complex | IDA PMID:28186186 P113 is a merozoite surface protein that binds the N terminu... | MODIFY | Summary: RH5 is a subunit of a multiprotein invasion complex comprising CyRPA, PfRipr and, through its N terminus, the GPI-anchored merozoite surface protein P113. Reason: The claim is right but GO:0032991 is the root complex term and says almost nothing. The complex RH5 belongs to is specific and structurally defined (cryo-EM in PMID:30542156), but GO currently has no term for it, so a proposed new term is given in proposed_new_terms and referenced here as an NTR replacement rather than leaving the root term or inventing an id. Proposed replacements: RH5-CyRPA-Ripr invasion complex Supporting Evidence: PMID:28186186 Here we use a sensitive assay that detects interactions between recombinant proteins to show that the glycosylphosphatidylinositol (GPI)-linked protein P113 interacts directly with the N terminus of unprocessed RH5, providing a mechanism by which the RH5 invasion complex is tethered to the merozoite surface. PMID:25583518 Here we have identified a conserved GPI-linked parasite protein, Cysteine-rich protective antigen (CyRPA) as an interacting partner of PfRH5-PfRipr that tethers the PfRH5/PfRipr/CyRPA multiprotein complex on the merozoite surface. PMID:30542156 Our structure identifies blades 4-6 of the Ξ²-propeller of CyRPA as contact sites for Rh5 and Ripr. |
| GO:0033644 host cell membrane | IDA PMID:30542156 Structure of Plasmodium falciparum Rh5-CyRPA-Ripr invasion c... | MODIFY | Summary: Rh5 inserts into the host erythrocyte membrane as part of the Rh5-CyRPA-Ripr complex. Reason: Correct but less specific than the evidence supports: the membrane in question is the erythrocyte plasma membrane, and the gene already carries the descendant GO:0020002 host cell plasma membrane with EXP evidence from this same work and from PMID:25583518 and PMID:27374406. Proposed replacements: host cell plasma membrane Supporting Evidence: PMID:30542156 Here we show that the Rh5-CyRPA-Ripr complex binds the erythrocyte cell line JK-1 significantly better than does Rh5 alone, and that this binding occurs through the insertion of Rh5 and Ripr into host membranes as a complex with high molecular weight. |
| GO:0034591 rhoptry lumen | IDA PMID:28409866 P. falciparum RH5-Basigin interaction induces changes in the... | ACCEPT | Summary: RH5 is contained within the rhoptry lumen in late schizonts before release. Reason: A soluble protein with a signal peptide stored inside a secretory organelle; the lumenal term is the precise location and is consistent with the rhoptry rows. Supporting Evidence: PMID:18827878 Thus, like the other RH ligands, PfRH5 is localized within the rhoptries, strongly suggesting a role in merozoite invasion. PMID:21909261 The PfRipr protein localises to the apical end of the merozoites in micronemes whilst PfRh5 is contained within rhoptries and both are released during invasion when they form a complex that is shed into the culture supernatant. |
| GO:0034591 rhoptry lumen | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic mapping of the UniProt 'rhoptry lumen' subcellular location to GO:0034591. Reason: Maps from a UniProt location that is itself experimentally supported for RH5; reinforces the IDA row. Supporting Evidence: PMID:18827878 Thus, like the other RH ligands, PfRH5 is localized within the rhoptries, strongly suggesting a role in merozoite invasion. |
| GO:0043655 host extracellular region | IDA PMID:21909261 An EGF-like protein forms a complex with PfRh5 and is requir... | ACCEPT | Summary: RH5 and PfRipr are released during invasion and shed into the surrounding medium. Reason: RH5 is released from the merozoite into the blood compartment of the host and acts there, at the surface of and between host cells. GO:0043655 sits under GO:0018995 host cellular component rather than under GO:0005576, so this is an independent, correctly host-scoped claim and not a duplicate of the extracellular region rows. Supporting Evidence: PMID:21909261 The PfRipr protein localises to the apical end of the merozoites in micronemes whilst PfRh5 is contained within rhoptries and both are released during invasion when they form a complex that is shed into the culture supernatant. |
| GO:0043655 host extracellular region | IDA PMID:27374406 Essential Role of the PfRh5/PfRipr/CyRPA Complex during Plas... | ACCEPT | Summary: RH5 is found at the interface between merozoite and erythrocyte, outside the host cell. Reason: RH5 is released from the merozoite into the blood compartment of the host and acts there, at the surface of and between host cells. GO:0043655 sits under GO:0018995 host cellular component rather than under GO:0005576, so this is an independent, correctly host-scoped claim and not a duplicate of the extracellular region rows. Supporting Evidence: PMID:27374406 Super-resolution microscopy revealed that PfRipr, CyRPA, and PfRh5 colocalize at the junction between merozoites and erythrocytes during invasion. |
| GO:0043655 host extracellular region | IDA PMID:28409866 P. falciparum RH5-Basigin interaction induces changes in the... | ACCEPT | Summary: RH5 acts on the erythrocyte from outside, engaging basigin on the host cell surface. Reason: RH5 is released from the merozoite into the blood compartment of the host and acts there, at the surface of and between host cells. GO:0043655 sits under GO:0018995 host cellular component rather than under GO:0005576, so this is an independent, correctly host-scoped claim and not a duplicate of the extracellular region rows. Supporting Evidence: PMID:28409866 We show that RH5-Basigin interaction on its own triggers a Ca2+ signal in the RBC resulting in changes in RBC cytoskeletal proteins phosphorylation and overall alterations in RBC cytoskeleton architecture. |
| GO:0044409 symbiont entry into host | IDA PMID:19000690 Reticulocyte-binding protein homologue 5 - an essential adhe... | MODIFY | Summary: RH5 is an essential adhesin of the merozoite acting at the point of commitment to erythrocyte invasion. Reason: The claim is correct, but GO:0044409 covers entry into the host body, tissues or cells alike, whereas the evidence is specifically about a merozoite entering an erythrocyte. Apicomplexan invasion is vacuole-mediated, in that the merozoite attaches, the erythrocyte membrane invaginates at the moving junction and closes behind the parasite to form the parasitophorous vacuole. That is the definition of the descendant GO:0085017 entry into host cell by a symbiont-containing vacuole, and it is the term GOA itself uses for P. falciparum invasion proteins (MSP1 by IDA, CSP by IMP). The intermediate GO:0046718 symbiont entry into host cell, which the gene also carries, is framed around breaching the membrane and releasing the symbiont or its genome into the cytoplasm, so it is both less specific and a poorer fit; these rows are refined to GO:0085017 instead. Proposed replacements: entry into host cell by a symbiont-containing vacuole Supporting Evidence: PMID:19000690 We hypothesise an essential role for the PfRh5 adhesin in erythrocyte selection and commitment to invasion. PMID:19000690 Furthermore, rabbit immune serum raised against a portion of the ecto-domain, inhibits parasite invasion in vitro. |
| GO:0044409 symbiont entry into host | IDA PMID:22080952 Basigin is a receptor essential for erythrocyte invasion by ... | MODIFY | Summary: Invasion in every strain tested depends on the RH5-basigin interaction. Reason: The claim is correct, but GO:0044409 covers entry into the host body, tissues or cells alike, whereas the evidence is specifically about a merozoite entering an erythrocyte. Apicomplexan invasion is vacuole-mediated, in that the merozoite attaches, the erythrocyte membrane invaginates at the moving junction and closes behind the parasite to form the parasitophorous vacuole. That is the definition of the descendant GO:0085017 entry into host cell by a symbiont-containing vacuole, and it is the term GOA itself uses for P. falciparum invasion proteins (MSP1 by IDA, CSP by IMP). The intermediate GO:0046718 symbiont entry into host cell, which the gene also carries, is framed around breaching the membrane and releasing the symbiont or its genome into the cytoplasm, so it is both less specific and a poorer fit; these rows are refined to GO:0085017 instead. Proposed replacements: entry into host cell by a symbiont-containing vacuole Supporting Evidence: PMID:22080952 By systematically screening a library of erythrocyte proteins, we have found that the Ok blood group antigen, basigin, is a receptor for PfRh5, a parasite ligand that is essential for blood stage growth. PMID:22080952 Erythrocyte invasion was potently inhibited by soluble basigin or by basigin knockdown, and invasion could be completely blocked using low concentrations of anti-basigin antibodies; importantly, these effects were observed across all laboratory-adapted and field strains tested. |
| GO:0044409 symbiont entry into host | IDA PMID:28409866 P. falciparum RH5-Basigin interaction induces changes in the... | MODIFY | Summary: RH5-basigin engagement triggers the host changes that precede junction formation and invasion. Reason: The claim is correct, but GO:0044409 covers entry into the host body, tissues or cells alike, whereas the evidence is specifically about a merozoite entering an erythrocyte. Apicomplexan invasion is vacuole-mediated, in that the merozoite attaches, the erythrocyte membrane invaginates at the moving junction and closes behind the parasite to form the parasitophorous vacuole. That is the definition of the descendant GO:0085017 entry into host cell by a symbiont-containing vacuole, and it is the term GOA itself uses for P. falciparum invasion proteins (MSP1 by IDA, CSP by IMP). The intermediate GO:0046718 symbiont entry into host cell, which the gene also carries, is framed around breaching the membrane and releasing the symbiont or its genome into the cytoplasm, so it is both less specific and a poorer fit; these rows are refined to GO:0085017 instead. Proposed replacements: entry into host cell by a symbiont-containing vacuole Supporting Evidence: PMID:28409866 We show that RH5-Basigin interaction on its own triggers a Ca2+ signal in the RBC resulting in changes in RBC cytoskeletal proteins phosphorylation and overall alterations in RBC cytoskeleton architecture. PMID:28409866 Antibodies targeting RH5 that block the signal prevent invasion before junction formation consistent with the Ca2+ signal in the RBC leading to rearrangement of the cytoskeleton required for invasion. |
| GO:0044409 symbiont entry into host | IMP PMID:25296023 Crystal structure of PfRh5, an essential P. falciparum ligan... | MODIFY | Summary: RH5 is the only essential invasion ligand of the PfRh family; its structure defines the basigin-binding surface. Reason: The claim is correct, but GO:0044409 covers entry into the host body, tissues or cells alike, whereas the evidence is specifically about a merozoite entering an erythrocyte. Apicomplexan invasion is vacuole-mediated, in that the merozoite attaches, the erythrocyte membrane invaginates at the moving junction and closes behind the parasite to form the parasitophorous vacuole. That is the definition of the descendant GO:0085017 entry into host cell by a symbiont-containing vacuole, and it is the term GOA itself uses for P. falciparum invasion proteins (MSP1 by IDA, CSP by IMP). The intermediate GO:0046718 symbiont entry into host cell, which the gene also carries, is framed around breaching the membrane and releasing the symbiont or its genome into the cytoplasm, so it is both less specific and a poorer fit; these rows are refined to GO:0085017 instead. Proposed replacements: entry into host cell by a symbiont-containing vacuole Supporting Evidence: PMID:25296023 PfRh5 binds the host receptor basigin. PMID:25296023 In this study, we have determined the crystal structure of PfRh5 using diffraction data to 2.18 Γ
resolution. |
| GO:0044409 symbiont entry into host | IMP PMID:28096331 One-step design of a stable variant of the malaria invasion ... | MODIFY | Summary: Basigin binding by RH5 is essential for erythrocyte invasion; stabilised variants retain it. Reason: The claim is correct, but GO:0044409 covers entry into the host body, tissues or cells alike, whereas the evidence is specifically about a merozoite entering an erythrocyte. Apicomplexan invasion is vacuole-mediated, in that the merozoite attaches, the erythrocyte membrane invaginates at the moving junction and closes behind the parasite to form the parasitophorous vacuole. That is the definition of the descendant GO:0085017 entry into host cell by a symbiont-containing vacuole, and it is the term GOA itself uses for P. falciparum invasion proteins (MSP1 by IDA, CSP by IMP). The intermediate GO:0046718 symbiont entry into host cell, which the gene also carries, is framed around breaching the membrane and releasing the symbiont or its genome into the cytoplasm, so it is both less specific and a poorer fit; these rows are refined to GO:0085017 instead. Proposed replacements: entry into host cell by a symbiont-containing vacuole Supporting Evidence: PMID:28096331 PfRH5 is released onto the surface of infective Plasmodium falciparum merozoites, binding to human basigin in an interaction that is essential for erythrocyte invasion ( 4 β 7 ). PMID:28096331 For instance, Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is essential for erythrocyte invasion, is highly conserved among field isolates, and elicits antibodies that neutralize in vitro and protect in an animal model, making it a leading malaria vaccine candidate. |
| GO:0044409 symbiont entry into host | IMP PMID:28186186 P113 is a merozoite surface protein that binds the N terminu... | MODIFY | Summary: RH5 must be tethered to the merozoite surface by P113 and engage basigin for invasion to proceed. Reason: The claim is correct, but GO:0044409 covers entry into the host body, tissues or cells alike, whereas the evidence is specifically about a merozoite entering an erythrocyte. Apicomplexan invasion is vacuole-mediated, in that the merozoite attaches, the erythrocyte membrane invaginates at the moving junction and closes behind the parasite to form the parasitophorous vacuole. That is the definition of the descendant GO:0085017 entry into host cell by a symbiont-containing vacuole, and it is the term GOA itself uses for P. falciparum invasion proteins (MSP1 by IDA, CSP by IMP). The intermediate GO:0046718 symbiont entry into host cell, which the gene also carries, is framed around breaching the membrane and releasing the symbiont or its genome into the cytoplasm, so it is both less specific and a poorer fit; these rows are refined to GO:0085017 instead. Proposed replacements: entry into host cell by a symbiont-containing vacuole Supporting Evidence: PMID:28186186 The role of RH5 as an invasion ligand was established by the identification of basigin as its erythrocyte receptor, and the demonstration that the RH5-basigin interaction was both essential and universally required for invasion9. PMID:28186186 Here we use a sensitive assay that detects interactions between recombinant proteins to show that the glycosylphosphatidylinositol (GPI)-linked protein P113 interacts directly with the N terminus of unprocessed RH5, providing a mechanism by which the RH5 invasion complex is tethered to the merozoite surface. |
| GO:0044409 symbiont entry into host | IMP PMID:28195038 Structure of the malaria vaccine candidate antigen CyRPA and... | MODIFY | Summary: Merozoites lacking RH5 adhere to erythrocytes but cannot attach irreversibly or invade. Reason: The claim is correct, but GO:0044409 covers entry into the host body, tissues or cells alike, whereas the evidence is specifically about a merozoite entering an erythrocyte. Apicomplexan invasion is vacuole-mediated, in that the merozoite attaches, the erythrocyte membrane invaginates at the moving junction and closes behind the parasite to form the parasitophorous vacuole. That is the definition of the descendant GO:0085017 entry into host cell by a symbiont-containing vacuole, and it is the term GOA itself uses for P. falciparum invasion proteins (MSP1 by IDA, CSP by IMP). The intermediate GO:0046718 symbiont entry into host cell, which the gene also carries, is framed around breaching the membrane and releasing the symbiont or its genome into the cytoplasm, so it is both less specific and a poorer fit; these rows are refined to GO:0085017 instead. Proposed replacements: entry into host cell by a symbiont-containing vacuole Supporting Evidence: PMID:28195038 While merozoites deficient in PfCyRPA or PfRH5 can still bind to erythrocytes, they do not attach irreversibly and cannot invade the host cells (Volz et al., 2016). PMID:28195038 Both in vitro and in vivo anti-PfCyRPA and anti-PfRH5 antibodies showed more potent parasite growth inhibitory activity in combination than on their own, supporting a combined delivery of PfCyRPA and PfRH5 in vaccines. |
| GO:0044409 symbiont entry into host | IMP PMID:28195530 Structural basis for inhibition of erythrocyte invasion by a... | MODIFY | Summary: The RH5/CyRPA/PfRipr complex binding to basigin is a key step of merozoite invasion. Reason: The claim is correct, but GO:0044409 covers entry into the host body, tissues or cells alike, whereas the evidence is specifically about a merozoite entering an erythrocyte. Apicomplexan invasion is vacuole-mediated, in that the merozoite attaches, the erythrocyte membrane invaginates at the moving junction and closes behind the parasite to form the parasitophorous vacuole. That is the definition of the descendant GO:0085017 entry into host cell by a symbiont-containing vacuole, and it is the term GOA itself uses for P. falciparum invasion proteins (MSP1 by IDA, CSP by IMP). The intermediate GO:0046718 symbiont entry into host cell, which the gene also carries, is framed around breaching the membrane and releasing the symbiont or its genome into the cytoplasm, so it is both less specific and a poorer fit; these rows are refined to GO:0085017 instead. Proposed replacements: entry into host cell by a symbiont-containing vacuole Supporting Evidence: PMID:28195530 We show CyRPA interacts directly with PfRh5. PMID:28195530 An invasion inhibitory monoclonal antibody to CyRPA blocks binding of CyRPA to PfRh5 and complex formation thus illuminating the molecular mechanism for inhibition of parasite growth. |
| GO:0044409 symbiont entry into host | IMP PMID:31204103 Human Antibodies that Slow Erythrocyte Invasion Potentiate M... | MODIFY | Summary: Human monoclonal antibodies against RH5 neutralise or slow erythrocyte invasion. Reason: The claim is correct, but GO:0044409 covers entry into the host body, tissues or cells alike, whereas the evidence is specifically about a merozoite entering an erythrocyte. Apicomplexan invasion is vacuole-mediated, in that the merozoite attaches, the erythrocyte membrane invaginates at the moving junction and closes behind the parasite to form the parasitophorous vacuole. That is the definition of the descendant GO:0085017 entry into host cell by a symbiont-containing vacuole, and it is the term GOA itself uses for P. falciparum invasion proteins (MSP1 by IDA, CSP by IMP). The intermediate GO:0046718 symbiont entry into host cell, which the gene also carries, is framed around breaching the membrane and releasing the symbiont or its genome into the cytoplasm, so it is both less specific and a poorer fit; these rows are refined to GO:0085017 instead. Proposed replacements: entry into host cell by a symbiont-containing vacuole Supporting Evidence: PMID:31204103 We also identify the epitope of a novel group of non-neutralizing antibodies that significantly reduce the speed of red blood cell invasion by the merozoite, thereby potentiating the effect of all neutralizing PfRH5 antibodies as well as synergizing with antibodies targeting other malaria invasion proteins. PMID:31204103 The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the leading target for next-generation vaccines against the disease-causing blood-stage of malaria. |
| GO:0044650 adhesion of symbiont to host cell | IEA GO_REF:0000108 | ACCEPT | Summary: Adhesion of the merozoite to the erythrocyte, inferred logically from RH5's host cell surface receptor binding activity. Reason: The inference is biologically correct and independently supported: merozoites deficient in RH5 still make initial contact with erythrocytes but fail to attach irreversibly, so RH5 performs the adhesion step itself rather than merely being required for a downstream event. Supporting Evidence: PMID:28195038 While merozoites deficient in PfCyRPA or PfRH5 can still bind to erythrocytes, they do not attach irreversibly and cannot invade the host cells (Volz et al., 2016). PMID:22080952 By systematically screening a library of erythrocyte proteins, we have found that the Ok blood group antigen, basigin, is a receptor for PfRh5, a parasite ligand that is essential for blood stage growth. |
| GO:0045177 apical part of cell | IDA PMID:27374406 Essential Role of the PfRh5/PfRipr/CyRPA Complex during Plas... | ACCEPT | Summary: RH5 is detected at the apical pole of the merozoite, where it colocalises with CyRPA and PfRipr at the point of contact with the erythrocyte. Reason: The merozoite is a strongly polarised cell with a defined apical end, and GO:0045177 is the general term for that region; RH5 is concentrated there after rhoptry discharge. The more specific apicomplexan organelle terms (GO:0020008 rhoptry, GO:0034591 rhoptry lumen) are already carried for the stored pool, and this row adds the post-secretion apical surface pool, so it is kept rather than merged into them. Supporting Evidence: PMID:27374406 Super-resolution microscopy revealed that PfRipr, CyRPA, and PfRh5 colocalize at the junction between merozoites and erythrocytes during invasion. PMID:21909261 The PfRipr protein localises to the apical end of the merozoites in micronemes whilst PfRh5 is contained within rhoptries and both are released during invasion when they form a complex that is shed into the culture supernatant. |
| GO:0046718 symbiont entry into host cell | EXP PMID:19000690 Reticulocyte-binding protein homologue 5 - an essential adhe... | MODIFY | Summary: RH5 is an essential adhesin required for merozoite entry into human erythrocytes; antibodies to its ectodomain inhibit invasion. Reason: RH5 executes the receptor-engagement step of merozoite entry rather than merely being necessary for it, so the process claim is right; but GO:0046718 is framed around breaching the membrane and releasing the symbiont or its genome into the cytoplasm, whereas the merozoite enters within a parasitophorous vacuole formed as the erythrocyte membrane invaginates and closes behind it. The descendant GO:0085017 entry into host cell by a symbiont-containing vacuole states exactly that, and is the term GOA uses for the other P. falciparum invasion proteins (MSP1, CSP). Proposed replacements: entry into host cell by a symbiont-containing vacuole Supporting Evidence: PMID:19000690 We hypothesise an essential role for the PfRh5 adhesin in erythrocyte selection and commitment to invasion. PMID:19000690 Furthermore, rabbit immune serum raised against a portion of the ecto-domain, inhibits parasite invasion in vitro. PMID:24212193 The function of the DBL and RBL proteins are redundant because knockout strains of all of the dbl and rbl genes except for PfRH5 have been generated and show insignificant loss of invasion efficiency7. |
| GO:0046718 symbiont entry into host cell | EXP PMID:22080952 Basigin is a receptor essential for erythrocyte invasion by ... | MODIFY | Summary: The RH5-basigin receptor-ligand pair is required for erythrocyte invasion in all P. falciparum strains tested. Reason: Core process annotation, supported by soluble-receptor competition, receptor knockdown and antibody blockade; refined for the same reason as the other GO:0046718 row, since apicomplexan merozoite entry is vacuole-mediated and is captured by the descendant GO:0085017. Proposed replacements: entry into host cell by a symbiont-containing vacuole Supporting Evidence: PMID:22080952 By systematically screening a library of erythrocyte proteins, we have found that the Ok blood group antigen, basigin, is a receptor for PfRh5, a parasite ligand that is essential for blood stage growth. PMID:22080952 Erythrocyte invasion was potently inhibited by soluble basigin or by basigin knockdown, and invasion could be completely blocked using low concentrations of anti-basigin antibodies; importantly, these effects were observed across all laboratory-adapted and field strains tested. |
| GO:0046789 host cell surface receptor binding | IPI PMID:22080952 Basigin is a receptor essential for erythrocyte invasion by ... | ACCEPT | Summary: RH5 binds basigin (CD147, Ok blood group antigen) on the erythrocyte surface; this is the receptor interaction that licenses invasion. Reason: This is RH5's core molecular function, identified by systematic receptor screening and confirmed structurally (PMID:25296023, PMID:30542156) and by host-tropism mapping (PMID:24297912). It is also the term to which the generic protein binding rows naming basigin are refined. Supporting Evidence: PMID:22080952 By systematically screening a library of erythrocyte proteins, we have found that the Ok blood group antigen, basigin, is a receptor for PfRh5, a parasite ligand that is essential for blood stage growth. PMID:22080952 Erythrocyte invasion was potently inhibited by soluble basigin or by basigin knockdown, and invasion could be completely blocked using low concentrations of anti-basigin antibodies; importantly, these effects were observed across all laboratory-adapted and field strains tested. PMID:25296023 PfRh5 binds the host receptor basigin. |
| GO:0141134 symbiont-mediated activation of host signal transduction pathway via agonism of host cell surface receptor | IDA PMID:28409866 P. falciparum RH5-Basigin interaction induces changes in the... | NEW | Summary: Engagement of host basigin by RH5 is by itself sufficient to trigger a Ca2+ signal in the erythrocyte, with downstream phosphorylation and remodelling of the host cytoskeleton; antibodies that block the signal block invasion before junction formation. Reason: RH5 performs this step itself: the agonism is the RH5-basigin binding event, shown with recombinant RH5 on erythrocytes in the absence of other parasite proteins (PMID:28409866), and the same requirement is seen for the assembled complex during invasion (PMID:27374406). The term was verified in OLS and is scoped from the symbiont's side, which is the correct direction for a parasite ligand acting on a host receptor. This is not covered by the entry/adhesion terms, which describe the parasite's own movement into the cell rather than its effect on host signalling, and it is not merely a necessity claim: the trigger is attributed to the interaction itself, not to RH5 being required for a later step. Supporting Evidence: PMID:28409866 We show that RH5-Basigin interaction on its own triggers a Ca2+ signal in the RBC resulting in changes in RBC cytoskeletal proteins phosphorylation and overall alterations in RBC cytoskeleton architecture. PMID:28409866 Antibodies targeting RH5 that block the signal prevent invasion before junction formation consistent with the Ca2+ signal in the RBC leading to rearrangement of the cytoskeleton required for invasion. PMID:27374406 PfRipr, CyRPA, and PfRipr/CyRPA/PfRh5-basigin complex is required for triggering the Ca(2+) release and establishing the tight junction. |
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Download this section (compressed HTML)Q: Does RH5 contribute structurally to pore or junction formation after membrane insertion, or is its role complete once basigin is engaged and the calcium signal delivered? The cryo-EM work shows RH5 and Ripr inserting into the host membrane, but what they form there is unknown.
Q: Which host kinase or channel transduces the RH5-basigin contact into the erythrocyte calcium flux, and is basigin dimerisation the proximal event? Answering this would show whether a symbiont-mediated perturbation of host cytoskeleton term (GO:0052039) should also be annotated to RH5 or belongs to a host protein.
Q: What is the function, if any, of the N-terminal region released by cleavage at 140/141 after P113 release - is it inert, or does it act on the erythrocyte independently?
Q: Is the high-affinity heparin binding of RH5 a property of the basigin-binding surface, and does any sulfated glycan on the erythrocyte or in plasma engage it physiologically?
Experiment: Reconstitute recombinant RH5, CyRPA and PfRipr with basigin-bearing liposomes or erythrocyte ghosts and test by electrophysiology and dye release whether the inserted complex forms a conductive pore, separating membrane insertion from junction formation.
Experiment: Use conditional knockdown of RH5 combined with live calcium imaging and phosphoproteomics of the erythrocyte to identify the host signalling chain between basigin engagement and cytoskeletal remodelling, and test candidate kinases with specific inhibitors on invasion kinetics.
Experiment: Express RH5 carrying a non-cleavable 140/141 site and a P113-binding-deficient N terminus in parasites to determine whether the release of RH5 from P113, and the fate of the cleaved N-terminal fragment, are separately required for invasion.
Experiment: Measure RH5 binding to basigin orthologues from a panel of great apes and to engineered basigin point mutants by surface plasmon resonance alongside invasion assays in the matching erythrocytes, to test quantitatively how receptor affinity maps onto host range.
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