Affinage · Plasmodium

Showing PF3D7_1133400 — AMA1 is a alias.

AMA1

PF3D7_1133400 · apical membrane antigen 1

Annotated
2026-09-08
98 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AMA1 (PF3D7_1133400) is a type I integral membrane protein of the apical complex that is essential for blood-stage survival and mediates the apical attachment and reorientation steps of host-cell invasion by Plasmodium merozoites (PMID:2701947, PMID:11115107, PMID:14688092, PMID:24571085). It matures within micronemes as an 83 kDa precursor that is proteolytically processed to a 66 kDa form (removal of an N-terminal prosequence) and translocates along subpellicular microtubules to the merozoite apex before relocating to the merozoite surface at about the time of erythrocyte invasion (PMID:11399764, PMID:12902400, PMID:2404781). The ectodomain is folded by eight intramolecular disulfide bonds into three PAN-motif subdomains, with domain I loops presenting polymorphic residues around a conserved hydrophobic groove that forms the receptor-binding pocket (PMID:8910611, PMID:16129835, PMID:15731407). Through this groove — including the conserved residue Tyr251 and a surface exposed by displacement of the domain II loop — AMA1 binds the extracellular segment of PfRON2, the molecular step that commits merozoites to invasion and triggers tight-junction formation; the endogenous moving junction is a 1:1:1:1 PfAMA1–PfRON2–PfRON4–PfRON5 complex in which AMA1 directly contacts the RBC membrane (PMID:19165323, PMID:22737069, PMID:21788485, PMID:16835460, PMID:18952195, PMID:42379167). AMA1 function additionally requires phosphorylation of its cytoplasmic tail at Ser610 by cAMP-dependent protein kinase A (PfPKA) (PMID:20532217, PMID:19283086), and following junction engagement the ectodomain is shed essentially to completion by the membrane-bound serine sheddase PfSUB2 at a single juxtamembrane site, leaving only a membrane stub carried into the host cell (PMID:12686561, PMID:16102004). Because domain I polymorphisms confer escape from invasion-inhibitory antibodies while the RON2-binding pocket remains conserved, AMA1 and the AMA1–RON2 interface are foci of vaccine and inhibitor design (PMID:15049818, PMID:11292751, PMID:22737069, PMID:24958881).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1989 Medium

    Establishing where AMA1 acts required first placing the protein in the cell; its identification as an integral membrane protein of the merozoite apical complex that reaches the surface near schizont rupture defined it as an invasion-stage molecule.

    Evidence Molecular cloning with immunoelectron microscopy and immunofluorescence in P. falciparum

    PMID:2404781 PMID:2701947

    Open questions at the time
    • Molecular function at the surface not yet defined
    • Precursor processing enzyme unknown
  2. 1996 High

    Understanding how the ectodomain is organized and why it is antigenically variable required mapping its covalent architecture; assignment of eight disulfide bonds defined three subdomains and showed polymorphic sites cluster into conformational epitopes.

    Evidence MS, N-terminal sequencing and HPLC of baculovirus-expressed P. chabaudi AMA1

    PMID:8910611

    Open questions at the time
    • 3D fold not yet resolved
    • Receptor-binding surface not localized
  3. 2000 High

    Whether AMA1 was dispensable or required was resolved genetically; failure to disrupt the gene combined with partial cross-species complementation established essentiality for blood-stage growth and functional conservation across species.

    Evidence Knockout attempts and trans-species complementation with P. chabaudi AMA1 in P. falciparum, invasion assays

    PMID:11115107

    Open questions at the time
    • Which invasion step AMA1 executes not defined
    • Molecular partners unidentified
  4. 2001 High

    Linking AMA1 to a defined invasion role required trafficking and processing detail plus functional interference; independent surface translocation of the processed 66 kDa form and antibody-mediated invasion block established AMA1 as a surface-acting invasion effector, with proteolytic maturation and shedding as regulatory events.

    Evidence Immunofluorescence trafficking analysis, microsequencing/MS cleavage-site mapping, and invasion-inhibition assays with anti-3D7 AMA1 antibodies

    PMID:11292751 PMID:11399764 PMID:12228305

    Open questions at the time
    • Shedding protease not yet identified
    • Erythrocyte receptor unknown
  5. 2003 High

    Defining the physical step AMA1 performs and how it is trafficked required ultrastructure and enzymology; microtubule-guided micronemal delivery, actin-independent surface shedding by the PfSUB2 serine sheddase at a single juxtamembrane site, and antibody evidence that AMA1 governs merozoite reorientation and apical attachment placed AMA1 at the reorientation/junction step.

    Evidence Immunoelectron microscopy, MS cleavage mapping, protease/cytochalasin D inhibitor studies, and inhibitory anti-P. knowlesi AMA1 mAb ultrastructural analysis

    PMID:12686561 PMID:12902400 PMID:14526103 PMID:14676185 PMID:14688092

    Open questions at the time
    • Direct receptor/partner at the junction not yet identified
    • Regulation of shedding timing unclear
  6. 2005 High

    Understanding the antigenic and receptor-binding basis of AMA1 required its atomic structure; crystal structures revealed PAN-domain architecture with polymorphic domain I loops surrounding a conserved hydrophobic trough, allelic exchange showed domain I polymorphisms drive antibody escape, and candidate erythrocyte interactions (domain III–Kx) and shedding-site chemistry were defined.

    Evidence X-ray crystallography of P. falciparum DI+II and P. vivax ectodomain, allelic-exchange transgenics, CHO-based binding/Kx-null invasion assays, MS mapping of the Thr517 shedding site

    PMID:15049818 PMID:15731407 PMID:15805191 PMID:16102004 PMID:16129835

    Open questions at the time
    • Physiological ligand of the hydrophobic trough still unknown
    • Kx interaction not integrated into a mechanistic model
  7. 2006 High

    Locating the functional inhibitory hotspot required epitope mapping and partner identification; peptide/antibody structures pinpointed the hydrophobic cleft and domain II loop as invasion-critical, and co-immunoprecipitation of PfAMA1 with PfRON4 first tied AMA1 to a conserved rhoptry-neck moving-junction complex.

    Evidence NMR of the R1 peptide, IgNAR and mAb 4G2 epitope mapping/co-crystals with functional invasion assays, and Co-IP with immuno-EM of PfRON4

    PMID:16177378 PMID:16835460 PMID:17192270 PMID:17997971

    Open questions at the time
    • Direct AMA1 partner in the pocket not yet identified (RON4 interaction indirect)
    • Complex stoichiometry unknown
  8. 2009 High

    Determining what the hydrophobic groove actually binds and how AMA1 is activated required residue-level and cytoplasmic-domain dissection; Tyr251 was shown essential for complex formation, the cytoplasmic tail was found dispensable for trafficking but essential and phosphoregulated for invasion, extending AMA1 control beyond the ectodomain.

    Evidence Site-directed mutagenesis with 4G2 competition Co-IP, and cytoplasmic-domain swap/GFP complementation with live imaging in transgenic P. falciparum

    PMID:19165323 PMID:19283086

    Open questions at the time
    • Identity of the pocket ligand still not proven to be RON2
    • Kinase and phosphosite not yet identified
  9. 2011 High

    Establishing the causal molecular trigger and its species-specificity required linking pocket occupancy to a defined invasion decision; PfRON2 binding to the AMA1 pocket was shown to commit merozoites to invasion and trigger junction formation, distinct from vacuole induction, while genetics revealed AMA1 is required for erythrocyte but not sporozoite invasion in P. berghei.

    Evidence PfRON2/PfRON4 Co-IP and localization, AMA1-pocket and RON2-cysteine mutagenesis, R1 competition with epistatic ordering, Ser610Ala mutagenesis with PfPKA inhibition, and conditional knockout in P. berghei / T. gondii

    PMID:18952195 PMID:20228060 PMID:20532217 PMID:21788485 PMID:22177563

    Open questions at the time
    • Atomic details of the AMA1–RON2 interface not yet resolved
    • How Ser610 phosphorylation couples to invasion mechanically unknown
  10. 2014 High

    Refining AMA1's function beyond entry required conditional depletion and structure; DiCre excision showed AMA1 is essential for invasion and additionally required for post-invasion sealing of the parasitophorous vacuole, and the AMA1–RON2 co-crystal defined the groove plus domain-II-loop-displacement interface that RON2 (and the mimetic R1) engage.

    Evidence Conditional DiCre knockdown with growth/invasion analysis, and X-ray co-crystallography of the AMA1–RON2 peptide complex with alanine-scanning mutagenesis

    PMID:22737069 PMID:24571085

    Open questions at the time
    • Mechanism of vacuole-sealing role not defined
    • Full native junction architecture not yet resolved
  11. 2026 High

    Resolving the assembled junction as it operates required a native structure; cryo-EM of the endogenous 1:1:1:1 PfAMA1–PfRON2–PfRON4–PfRON5 unit from invasion-stalled parasites showed RON2 anchored in the RBC membrane displaying an extracellular handle for AMA1, AMA1 directly contacting the RBC membrane, and a RON2/4/5 platform inserting amphipathic helices into the host bilayer, while MD/mutagenesis refined the late DII-loop-closing binding step.

    Evidence Cryo-EM of endogenous moving-junction complex with computational inhibitor design, and molecular dynamics with mutagenesis/binding validation of the DII loop

    PMID:40067319 PMID:42379167

    Open questions at the time
    • Dynamics of AMA1 conformational change during junction traversal not fully resolved
    • How PfSUB2 shedding is coordinated with the assembled junction unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AMA1 mechanically couples its RON2-engaged ectodomain and Ser610-phosphorylated cytoplasmic tail to the actomyosin motor to drive host-membrane remodeling and vacuole sealing remains unresolved.
  • No structure of the phosphorylated cytoplasmic tail engaged with motor components
  • Mechanochemical link between junction engagement and force transmission undefined
  • Molecular basis of the post-invasion vacuole-sealing role unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
KX ERYTHROCYTE MEMBRANE PROTEIN (BINDS DOMAIN III AFTER TRYPSIN TREATMENT) [#15]PFPKA (CAMP-DEPENDENT PROTEIN KINASE A; PHOSPHORYLATES CYTOPLASMIC SER610) [#25]PFRON2 (RHOPTRY NECK PROTEIN; BINDS AMA1 HYDROPHOBIC GROOVE) [#26, #28, #21, #32, #31]PFRON4 [#19, #21, #32]PFRON5 [#32]PFSUB2 (MEMBRANE-BOUND SERINE SHEDDASE THAT SHEDS THE ECTODOMAIN) [#7]
Complex memberships
PfAMA1-PfRON2-PfRON4 complex [#21]PfAMA1-PfRON2-PfRON4-PfRON5 moving junction complex (1:1:1:1) [#32]PfAMA1-PfRON4 co-immunoprecipitated complex [#19]

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 PfAMA1 (apical membrane antigen 1) is an integral membrane protein located in the apical complex of P. falciparum merozoites and is transported to the merozoite surface near the time of schizont rupture. Molecular cloning and subcellular localization by immunoelectron microscopy/immunofluorescence Molecular and cellular biology Medium 2701947
1990 PfAMA1 is localized to the neck region of the rhoptry organelle in P. falciparum merozoites (not the rhoptry body), is Triton X-114 soluble (membrane-associated), and its 80 kDa precursor is immediately processed to a 62 kDa product upon synthesis; it is detectable on the merozoite surface but not in ring-infected erythrocytes. Immunoelectron microscopy, Triton X-114 phase separation, pulse-chase metabolic labeling, 2D gel electrophoresis, immunoblot Experimental parasitology Medium 2404781
1996 All 16 conserved cysteine residues of AMA1 are incorporated into 8 intramolecular disulfide bonds that define three nonoverlapping subdomains within the AMA1 ectodomain; six bonds were assigned unequivocally by mass spectrometry and N-terminal sequencing of reduced/non-reduced tryptic digests. The disulfide bond pattern clusters polymorphic sites in subdomains II and III, consistent with immune-selection of conformational epitopes. Reversed-phase HPLC, N-terminal sequencing, electrospray-ionization mass spectrometry of tryptic digests from baculovirus-expressed P. chabaudi AMA1 The Journal of biological chemistry High 8910611
2000 PfAMA1 is essential for blood-stage growth in P. falciparum; attempts to disrupt the Pfama1 gene by knock-out failed, but trans-species complementation with P. chabaudi AMA1 (PcAMA1) restored at least 35% of PfAMA1 function in human red cells, and PcAMA1 expression in P. falciparum increased efficiency of murine erythrocyte invasion. Homologous recombination targeting, trans-species complementation with transgenic parasites, erythrocyte invasion assay Molecular microbiology High 11115107
2001 PfAMA1 unprocessed precursor localizes to microneme organelles in intraerythrocytic schizonts; the processed (mature) form independently translocates from micronemes to the merozoite surface, independently of another microneme protein EBA175. Immunofluorescence, co-localization microscopy of PfAMA1 and EBA175 Infection and immunity Medium 12228305
2001 Anti-PfAMA1 antibodies inhibit invasion of erythrocytes by P. falciparum merozoites; inhibitory antibodies target both conserved and strain-specific epitopes within the ectodomain, with the majority reacting with strain-specific epitopes in domain I (the most polymorphic N-terminal disulfide-bonded domain). In vitro erythrocyte invasion inhibition assay with rabbit and affinity-purified human antibodies against recombinant 3D7 AMA1 ectodomain Infection and immunity High 11292751
2001 PfAMA1 is processed from an 83 kDa precursor (PfAMA1(83)) to a 66 kDa form (PfAMA1(66)) by cleavage at a specific site (removing the N-terminal prosequence/domain I propeptide); PfAMA1(66) selectively translocates to the merozoite surface at about the time of erythrocyte invasion and is then further proteolytically cleaved at one of two alternative sites (between domains II and III, or membrane-proximal), shedding 44 and 48 kDa soluble ectodomain fragments. PfAMA1 is not modified by N-linked oligosaccharides. Direct microsequencing, mass spectrometric peptide mass fingerprinting, pulse-chase experiments, immunoblot The Journal of biological chemistry High 11399764
2003 PfAMA1 ectodomain shedding from the merozoite surface occurs via a single cleavage site 29 residues from the predicted transmembrane domain, mediated by the same membrane-bound parasite serine sheddase (PfSUB2) that sheds the MSP-1 complex. Translocation and shedding of PfAMA1 is an actin-independent process. Mass spectrometric mapping of cleavage products, protease inhibitor studies, cytochalasin D actin inhibition assay The Journal of biological chemistry High 12686561
2003 PfAMA1 is expressed in P. falciparum sporozoites and is lost after invasion of hepatocytes; anti-AMA1 antibodies inhibit sporozoite invasion of hepatocytes. Upon microneme exocytosis, PfAMA1 (like TRAP) relocates to the sporozoite surface and is proteolytically cleaved and shed; serine protease inhibitors block this processing and shedding and inhibit sporozoite infectivity. Immunofluorescence, invasion inhibition assay with anti-AMA1 antibodies, serine protease inhibitor treatment, Western blot The Journal of biological chemistry Medium 14676185
2003 PfAMA1 is translocated within micronemes along subpellicular microtubules from near the nucleus to the merozoite apex during merozoite development, where micronemes dock with rhoptry tips. PfAMA1 antibodies label the peripheries of translocating and mature micronemes but not rhoptries, confirming its micronemal localization. Immunoelectron microscopy with polyclonal anti-PfAMA1 antibodies on developing schizonts Journal of cell science Medium 12902400
2003 Invasion-inhibitory IgG antibodies against correctly folded PfAMA1 block proteolytic processing of AMA1 (reduce the 44 and 48 kDa products, increase 66 and 52 kDa forms on merozoites) and prevent circumferential redistribution of AMA1 on the merozoite surface. Monovalent Fab fragments also inhibit invasion and cause accumulation of 66 and 52 kDa forms without cross-linking. Chymostatin and Ca2+ chelators also inhibit breakdown of the 66 kDa form. In vitro invasion inhibition assay, immunoblot of AMA1 processing intermediates, antibody cross-linking/trapping experiments, Fab fragment preparation Proceedings of the National Academy of Sciences of the United States of America Medium 14526103
2004 PfAMA1 mediates the close (junctional) apical attachment of merozoites to erythrocytes and is required for merozoite reorientation; an invasion-inhibitory monoclonal antibody against P. knowlesi AMA1 (MAb R31C2) allows initial long-range contact (12 nm) but prevents merozoite reorientation and subsequent tight junctional apical contact. Ultrastructural analysis by electron microscopy of P. knowlesi merozoites incubated with inhibitory monoclonal antibody Infection and immunity High 14688092
2004 Sequence polymorphisms within PfAMA1 (specifically in domain I) directly confer evasion of invasion-inhibitory antibodies; transgenic P. falciparum expressing heterologous AMA1 alleles differ in susceptibility to allele-specific inhibitory antibodies, and exchange of polymorphic domain 1 residues in a chimeric AMA1 affects antibody recognition. Allelic exchange transgenesis, in vitro invasion inhibition assays with allele-specific antibodies, chimeric AMA1 parasite lines Molecular microbiology High 15049818
2005 The crystal structure of PfAMA1 domains I+II reveals two intimately associated PAN domains; domain I contains long loops forming a scaffold for numerous polymorphic residues exclusively on one side of the molecule, surrounding a conserved hydrophobic trough predicted to be the receptor binding pocket. X-ray crystallography Proceedings of the National Academy of Sciences of the United States of America High 16129835
2005 The crystal structure of the complete ectoplasmic region of AMA1 from P. vivax (three domains) at 1.8 Å resolution shows that domains I and II belong to the PAN motif superfamily implicated in receptor binding; the epitope of an invasion-inhibitory monoclonal antibody specific for P. falciparum AMA1 was mapped and modeled onto the structure, suggesting domain II plays a critical part in receptor binding during invasion. X-ray crystallography at 1.8 Å, epitope mapping by mutagenesis, modeling Science (New York, N.Y.) High 15731407
2005 Domain III of PfAMA1 binds to the erythrocyte membrane protein Kx after trypsin treatment; neither domains I/II nor the full ectodomain bind untreated erythrocytes. Invasion of Kx-null (McLeod) erythrocytes by P. falciparum is significantly reduced, indicating a role for AMA1-Kx interaction in invasion. CHO-K1 cell surface expression of AMA1 domain constructs, erythrocyte binding assay with trypsin-treated and genetically mutant RBCs, P. falciparum invasion assay with Kx-null erythrocytes Proceedings of the National Academy of Sciences of the United States of America Medium 15805191
2005 PfAMA1 shedding during erythrocyte invasion goes essentially to completion via a single juxtamembrane sheddase cleavage at Thr517; only the juxtamembrane ectodomain stub is carried into the host cell and remains on the plasma membrane of the intracellular ring-stage parasite. When normal shedding is inhibited, PfAMA1 can be cleaved at an intramembrane rhomboid-like site, and PfAMA1 is susceptible to Drosophila rhomboid-1 cleavage in vitro, but is not normally processed this way. Mass spectrometry mapping of cleavage products, invasion assay with sheddase inhibitors, Drosophila rhomboid-1 in vitro cleavage assay, immunofluorescence of ring-stage parasites Molecular microbiology High 16102004
2005 An invasion-inhibitory peptide (R1) from a random phage display library binds the hydrophobic trough of PfAMA1 in a conformation-dependent, strain-specific manner and inhibits merozoite invasion of erythrocytes; NMR solution structure of R1 shows two structured regions (hydrophobic residues 5-10 and polar residues 13-17) that target a binding hot spot also recognized by other invasion-inhibitory peptides and monoclonal antibodies. Phage display peptide selection, erythrocyte invasion inhibition assay, NMR spectroscopy, competition binding assays Infection and immunity High 16177378
2006 The invasion-inhibitory monoclonal antibody 4G2 epitope lies exclusively within the domain II loop of PfAMA1; purified Fab fragments of 4G2 inhibit invasion more efficiently than the intact mAb, indicating the epitope is within a functionally critical region and invasion inhibition is not due solely to steric effects. The residues critical for 4G2 binding were mapped by alanine-scanning mutagenesis of a synthetic PfAMA1 gene whose function was validated by complementation. Synthetic gene mutagenesis, functional complementation in P. falciparum, invasion inhibition with Fab vs intact IgG, alanine-scanning epitope mapping The Journal of biological chemistry High 17192270
2006 PfAMA1 co-immunoprecipitates with PfRON4, the P. falciparum homologue of TgRON4, a secreted rhoptry neck protein that forms the moving junction in T. gondii; PfRON4 originates in rhoptry necks, indicating a conserved microneme-rhoptry collaboration at the moving junction across Apicomplexa. Co-immunoprecipitation, immunoelectron microscopy for PfRON4 localization Eukaryotic cell Medium 16835460
2007 An IgNAR single-variable-domain antibody targeting the conserved hydrophobic cleft of PfAMA1 inhibits erythrocyte invasion; co-crystal structures of two IgNAR-AMA1 complexes show extended CDR3 loops penetrating deep into the hydrophobic cleft contacting residues conserved across parasite species. X-ray co-crystallography, erythrocyte invasion inhibition assay, affinity measurement by surface plasmon resonance, targeted mutagenesis Structure (London, England : 1993) High 17997971
2008 PfRON2 (a rhoptry neck protein) forms a complex with PfAMA1 and PfRON4 in P. falciparum; PfRON2 transcription peaks at the mature schizont stage and the protein is expressed at the rhoptry neck in merozoites; co-immunoprecipitation shows PfRON2, PfRON4, and PfAMA1 form a complex, conserved from T. gondii. PfRON2 is not a component of the PfRhopH complex. Co-immunoprecipitation, immunofluorescence, immunoelectron microscopy Parasitology international Medium 18952195
2009 The invasion-inhibitory monoclonal antibody 4G2 cannot bind PfAMA1 when PfAMA1 is in a complex with its partner proteins; a single completely conserved PfAMA1 residue Tyr251, lying within a conserved hydrophobic groove adjacent to the 4G2 epitope, is required for complex formation. mAb 4G2 thus inhibits invasion by preventing PfAMA1 from interacting with other components of the invasion complex. Co-immunoprecipitation, site-directed mutagenesis of PfAMA1, competitive binding assay with mAb 4G2 PLoS pathogens High 19165323
2009 The cytoplasmic domain of PfAMA1 is not required for correct trafficking and surface translocation but is essential for AMA1 function during erythrocyte invasion; AMA1 acts at the time of primary contact/moving junction formation upstream of entry. The cytoplasmic domain is phosphorylated, and mutational analysis suggests phosphorylation plays an important role in invasion. Heterologous cytoplasmic domains from P. vivax and P. berghei AMA1 functionally substitute, but those from EBA-175 or Rh2b do not. Live video microscopy, complementation assay with GFP-tagged AMA1, cytoplasmic domain exchange constructs in transgenic P. falciparum, phosphorylation analysis PLoS pathogens High 19283086
2010 The invasion-inhibitory peptide R1 binds the PfAMA1 hydrophobic trough and prevents PfAMA1 interaction with the PfRON complex (RON2/RON4/RON5). The AMA1-RON complex forms after merozoite reorientation and engagement of the actomyosin motor but before rhoptry release; this interaction is proposed to be essential for secretion of rhoptry contents necessary for parasitophorous vacuole establishment. In vitro invasion inhibition assay, co-immunoprecipitation, competitive binding assay with R1 peptide, epistatic ordering by pharmacological inhibitors of invasion steps The Journal of biological chemistry Medium 20228060
2010 The cytoplasmic tail of PfAMA1 is phosphorylated at serine 610 by cAMP-dependent protein kinase A (PfPKA); mutation of Ser610 to alanine abolishes in vivo phosphorylation and dramatically impedes erythrocyte invasion. Mass spectrometry-based phosphorylation mapping, in vivo mutagenesis (Ser610Ala) in transgenic P. falciparum, invasion assay, pharmacological PKA inhibition PLoS pathogens High 20532217
2011 Binding of RON2 to the hydrophobic pocket of PfAMA1 is the molecular step that commits P. falciparum merozoites to RBC invasion and triggers junction formation; two conserved disulfide-linked cysteines in the RON2 peptide are critical for binding to the AMA1 pocket. Anti-AMA1 pocket antibodies block both junction formation and parasitophorous vacuole induction, while the RON2 peptide blocks junction formation but not parasitophorous vacuole formation, indicating these are molecularly distinct steps. Antibody inhibition assays targeting the hydrophobic pocket, AMA1 pocket mutagenesis, invasion inhibition assay with RON2 peptide, electron microscopy of junction formation Proceedings of the National Academy of Sciences of the United States of America High 21788485
2011 In P. berghei, AMA1 is important for merozoite invasion of erythrocytes but is dispensable for sporozoite invasion of hepatocytes (where RON4 acts independently of AMA1). In T. gondii tachyzoites, AMA1 is dispensable for normal RON4 ring and tight junction assembly but enhances tachyzoite apposition and internalization frequency. Conditional knockout/knockdown in P. berghei, invasion assay (erythrocyte and hepatocyte), genetic and functional analysis in T. gondii Cell host & microbe High 22177563
2012 The crystal structure of PfAMA1 in complex with a peptide from the extracellular region of PfRON2 reveals that the receptor-binding site of PfAMA1 comprises the hydrophobic groove and a region exposed by displacement of the flexible domain II loop. Key contact residues of PfRON2 and PfAMA1 were identified by mutagenesis and abrogated recombinant protein binding. The PfRON2 peptide inhibits erythrocyte invasion regardless of AMA1 polymorphisms. The invasion-inhibitory phage display peptide R1 structurally mimics PfRON2. X-ray crystallography of AMA1-RON2 peptide complex, alanine-scanning mutagenesis, binding assays with recombinant proteins, erythrocyte invasion inhibition assay PLoS pathogens High 22737069
2014 Conditional DiCre-mediated excision of the Pfama1 gene in P. falciparum results in ~80% decreased AMA1 expression within one intraerythrocytic growth cycle, reduces growth by 40%, and causes a post-invasion defect in sealing of the parasitophorous vacuole; demonstrating AMA1 is essential for merozoite invasion and plays a role in resealing of the red blood cell after invasion. Conditional knockdown using dimerizable Cre recombinase (DiCre) with loxP-flanked Pfama1 gene, growth assay, invasion efficiency analysis Cellular microbiology High 24571085
2014 Immunization with a PfAMA1-RON2 peptide complex (but not AMA1 alone) provides complete protection against lethal P. yoelii challenge in mice, and IgG from complex-immunized mice transfers protection; IgG from PfAMA1-RON2-immunized animals shows enhanced invasion inhibition compared with AMA1-alone IgG, associated with a shift in antibody specificity toward loop regions surrounding the RON2 binding site. Mouse immunization, passive IgG transfer, in vitro invasion inhibition assay, epitope mapping Proceedings of the National Academy of Sciences of the United States of America Medium 24958881
2025 The domain II (DII) loop of PfAMA1 plays a critical role in the late-stage binding event with PfRON2; computational simulation and experimental validation identified key amino acid residues in the PfRON2 helix essential for binding in the post-binding/loop-closing stage of the AMA1-RON2 interaction. Molecular dynamics simulation of DII loop dynamics, experimental validation of key residues by mutagenesis and binding assays Chembiochem : a European journal of chemical biology Medium 40067319
2026 The endogenous structure of the moving junction basic repeating unit from invasion-stalled P. falciparum parasites is a 1:1:1:1 complex of PfAMA1, PfRON2, PfRON4, and PfRON5 (sailboat-shaped). PfRON2 has two transmembrane helices that anchor the complex in the RBC membrane and display an extracellular handle for PfAMA1 binding; PfAMA1 directly contacts the RBC membrane. PfRON2/4/5 form a large basic platform inside the RBC that electrostatically engages the RBC membrane and inserts seven amphipathic helices into the bilayer, suggesting active host-membrane remodeling. Cryo-EM structure determination of endogenous moving junction complex purified from invasion-stalled P. falciparum parasites; computational protein design of inhibitory binder Cell High 42379167

Source papers

Stage 0 corpus · 98 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Specificity of the protective antibody response to apical membrane antigen 1. Infection and immunity 273 11292751
2000 Apical membrane antigen 1 plays a central role in erythrocyte invasion by Plasmodium species. Molecular microbiology 266 11115107
2003 A role for apical membrane antigen 1 during invasion of hepatocytes by Plasmodium falciparum sporozoites. The Journal of biological chemistry 264 14676185
2011 Binding of Plasmodium merozoite proteins RON2 and AMA1 triggers commitment to invasion. Proceedings of the National Academy of Sciences of the United States of America 244 21788485
2008 Apical membrane antigen 1: a malaria vaccine candidate in review. Trends in parasitology 232 18226584
1989 Integral membrane protein located in the apical complex of Plasmodium falciparum. Molecular and cellular biology 229 2701947
2005 Phase 1 clinical trial of apical membrane antigen 1: an asexual blood-stage vaccine for Plasmodium falciparum malaria. Infection and immunity 226 15908397
2002 In vitro studies with recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1): production and activity of an AMA1 vaccine and generation of a multiallelic response. Infection and immunity 224 12438374
2010 Interaction between Plasmodium falciparum apical membrane antigen 1 and the rhoptry neck protein complex defines a key step in the erythrocyte invasion process of malaria parasites. The Journal of biological chemistry 213 20228060
1998 Genetic polymorphism and natural selection in the malaria parasite Plasmodium falciparum. Genetics 213 9584096
1996 The disulfide bond structure of Plasmodium apical membrane antigen-1. The Journal of biological chemistry 213 8910611
2001 Strong diversifying selection on domains of the Plasmodium falciparum apical membrane antigen 1 gene. Genetics 197 11514442
1996 Protective immune responses to apical membrane antigen 1 of Plasmodium chabaudi involve recognition of strain-specific epitopes. Infection and immunity 195 8757869
2008 Wheat germ cell-free system-based production of malaria proteins for discovery of novel vaccine candidates. Infection and immunity 182 18268027
2005 Structure of AMA1 from Plasmodium falciparum reveals a clustering of polymorphisms that surround a conserved hydrophobic pocket. Proceedings of the National Academy of Sciences of the United States of America 174 16129835
2009 Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-1) administered in adjuvant system AS01B or AS02A. PloS one 169 19390585
2004 Apical membrane antigen 1, a major malaria vaccine candidate, mediates the close attachment of invasive merozoites to host red blood cells. Infection and immunity 168 14688092
2004 Human antibodies to recombinant protein constructs of Plasmodium falciparum Apical Membrane Antigen 1 (AMA1) and their associations with protection from malaria. Vaccine 168 15542195
2005 Crystal structure of the malaria vaccine candidate apical membrane antigen 1. Science (New York, N.Y.) 165 15731407
2002 High-level expression of the malaria blood-stage vaccine candidate Plasmodium falciparum apical membrane antigen 1 and induction of antibodies that inhibit erythrocyte invasion. Infection and immunity 165 12117958
1995 Natural selection on Plasmodium surface proteins. Molecular and biochemical parasitology 163 7630387
2002 Vaccination of monkeys with recombinant Plasmodium falciparum apical membrane antigen 1 confers protection against blood-stage malaria. Infection and immunity 158 12438375
2004 Allelic polymorphisms in apical membrane antigen-1 are responsible for evasion of antibody-mediated inhibition in Plasmodium falciparum. Molecular microbiology 153 15049818
2007 IgG antibody responses to Plasmodium falciparum merozoite antigens in Kenyan children have a short half-life. Malaria journal 152 17598897
2002 Independent translocation of two micronemal proteins in developing Plasmodium falciparum merozoites. Infection and immunity 152 12228305
2009 An inhibitory antibody blocks interactions between components of the malarial invasion machinery. PLoS pathogens 140 19165323
2008 Rhoptry neck protein RON2 forms a complex with microneme protein AMA1 in Plasmodium falciparum merozoites. Parasitology international 140 18952195
2001 Proteolytic processing and primary structure of Plasmodium falciparum apical membrane antigen-1. The Journal of biological chemistry 133 11399764
2012 Phase Ia clinical evaluation of the safety and immunogenicity of the Plasmodium falciparum blood-stage antigen AMA1 in ChAd63 and MVA vaccine vectors. PloS one 131 22363582
2006 Plasmodium falciparum AMA1 binds a rhoptry neck protein homologous to TgRON4, a component of the moving junction in Toxoplasma gondii. Eukaryotic cell 127 16835460
2010 Using serological measures to monitor changes in malaria transmission in Vanuatu. Malaria journal 126 20553604
2003 Plasmodium falciparum apical membrane antigen 1 (PfAMA-1) is translocated within micronemes along subpellicular microtubules during merozoite development. Journal of cell science 120 12902400
2008 Cohort study of the association of antibody levels to AMA1, MSP119, MSP3 and GLURP with protection from clinical malaria in Ghanaian children. Malaria journal 116 18664257
2003 A single malaria merozoite serine protease mediates shedding of multiple surface proteins by juxtamembrane cleavage. The Journal of biological chemistry 116 12686561
2012 Structural and functional insights into the malaria parasite moving junction complex. PLoS pathogens 115 22737069
2012 Enhancing blockade of Plasmodium falciparum erythrocyte invasion: assessing combinations of antibodies against PfRH5 and other merozoite antigens. PLoS pathogens 112 23144611
2010 Protein kinase a dependent phosphorylation of apical membrane antigen 1 plays an important role in erythrocyte invasion by the malaria parasite. PLoS pathogens 112 20532217
2009 Functional analysis of the leading malaria vaccine candidate AMA-1 reveals an essential role for the cytoplasmic domain in the invasion process. PLoS pathogens 112 19283086
2003 Geographical structure of diversity and differences between symptomatic and asymptomatic infections for Plasmodium falciparum vaccine candidate AMA1. Infection and immunity 110 12595459
2011 Independent roles of apical membrane antigen 1 and rhoptry neck proteins during host cell invasion by apicomplexa. Cell host & microbe 101 22177563
2002 Purification, characterization, and immunogenicity of the refolded ectodomain of the Plasmodium falciparum apical membrane antigen 1 expressed in Escherichia coli. Infection and immunity 101 12011004
2000 Immunization with parasite-derived apical membrane antigen 1 or passive immunization with a specific monoclonal antibody protects BALB/c mice against lethal Plasmodium yoelii yoelii YM blood-stage infection. Infection and immunity 99 10768987
2001 Polymorphism in the gene encoding the apical membrane antigen-1 (AMA-1) of Plasmodium falciparum. X. Asembo Bay Cohort Project. Molecular and biochemical parasitology 98 11295182
2000 Plasmodium vivax synonymous substitution frequencies, evolution and population structure deduced from diversity in AMA 1 and MSP 1 genes. Molecular and biochemical parasitology 97 10802318
1990 Plasmodium falciparum: two antigens of similar size are located in different compartments of the rhoptry. Experimental parasitology 97 2404781
2003 Invasion-inhibitory antibodies inhibit proteolytic processing of apical membrane antigen 1 of Plasmodium falciparum merozoites. Proceedings of the National Academy of Sciences of the United States of America 96 14526103
2005 Binding hot spot for invasion inhibitory molecules on Plasmodium falciparum apical membrane antigen 1. Infection and immunity 95 16177378
2008 Phase 1 trial of AMA1-C1/Alhydrogel plus CPG 7909: an asexual blood-stage vaccine for Plasmodium falciparum malaria. PloS one 94 18698359
2014 Conditional expression of apical membrane antigen 1 in Plasmodium falciparum shows it is required for erythrocyte invasion by merozoites. Cellular microbiology 93 24571085
2008 A diversity-covering approach to immunization with Plasmodium falciparum apical membrane antigen 1 induces broader allelic recognition and growth inhibition responses in rabbits. Infection and immunity 93 18378635
2007 Structure of an IgNAR-AMA1 complex: targeting a conserved hydrophobic cleft broadens malarial strain recognition. Structure (London, England : 1993) 93 17997971
2005 A human phase 1 vaccine clinical trial of the Plasmodium falciparum malaria vaccine candidate apical membrane antigen 1 in Montanide ISA720 adjuvant. Vaccine 93 15811655
2015 Recent advances in recombinant protein-based malaria vaccines. Vaccine 92 26458807
2006 Fine mapping of an epitope recognized by an invasion-inhibitory monoclonal antibody on the malaria vaccine candidate apical membrane antigen 1. The Journal of biological chemistry 92 17192270
2016 Demonstration of the Blood-Stage Plasmodium falciparum Controlled Human Malaria Infection Model to Assess Efficacy of the P. falciparum Apical Membrane Antigen 1 Vaccine, FMP2.1/AS01. The Journal of infectious diseases 89 26908756
2005 Structural comparison of apical membrane antigen 1 orthologues and paralogues in apicomplexan parasites. Molecular and biochemical parasitology 82 16154214
2004 Selection and affinity maturation of IgNAR variable domains targeting Plasmodium falciparum AMA1. Proteins 82 14997552
2008 Population structure of the genes encoding the polymorphic Plasmodium falciparum apical membrane antigen 1: implications for vaccine design. Proceedings of the National Academy of Sciences of the United States of America 80 18515425
2007 Phase I dose escalation safety and immunogenicity trial of Plasmodium falciparum apical membrane protein (AMA-1) FMP2.1, adjuvanted with AS02A, in malaria-naïve adults at the Walter Reed Army Institute of Research. Vaccine 80 17442466
2001 Rapid and precise epitope mapping of monoclonal antibodies against Plasmodium falciparum AMA1 by combined phage display of fragments and random peptides. Protein engineering 80 11707616
1999 High-level expression of Plasmodium vivax apical membrane antigen 1 (AMA-1) in Pichia pastoris: strong immunogenicity in Macaca mulatta immunized with P. vivax AMA-1 and adjuvant SBAS2. Infection and immunity 80 9864194
2014 Immunization with a functional protein complex required for erythrocyte invasion protects against lethal malaria. Proceedings of the National Academy of Sciences of the United States of America 79 24958881
2003 Induction of parasite growth-inhibitory antibodies by a virosomal formulation of a peptidomimetic of loop I from domain III of Plasmodium falciparum apical membrane antigen 1. Infection and immunity 79 12874357
2008 Safety and immunogenicity of a recombinant Plasmodium falciparum AMA1 malaria vaccine adjuvanted with Alhydrogel, Montanide ISA 720 or AS02. PloS one 78 19093004
2005 Distinct mechanisms govern proteolytic shedding of a key invasion protein in apicomplexan pathogens. Molecular microbiology 78 16102004
2009 High antibody titer against apical membrane antigen-1 is required to protect against malaria in the Aotus model. PloS one 76 19997632
2004 Antibody response of naturally infected individuals to recombinant Plasmodium vivax apical membrane antigen-1. International journal for parasitology 76 15710439
2013 Overcoming antigenic diversity by enhancing the immunogenicity of conserved epitopes on the malaria vaccine candidate apical membrane antigen-1. PLoS pathogens 73 24385910
2010 Plasmodium vivax: induction of CD4+CD25+FoxP3+ regulatory T cells during infection are directly associated with level of circulating parasites. PloS one 71 20224778
2000 Molecular characterisation of Plasmodium reichenowi apical membrane antigen-1 (AMA-1), comparison with P. falciparum AMA-1, and antibody-mediated inhibition of red cell invasion. Molecular and biochemical parasitology 70 10960173
2009 Anti-apical-membrane-antigen-1 antibody is more effective than anti-42-kilodalton-merozoite-surface-protein-1 antibody in inhibiting plasmodium falciparum growth, as determined by the in vitro growth inhibition assay. Clinical and vaccine immunology : CVI 69 19439523
2005 Allele specificity of naturally acquired antibody responses against Plasmodium falciparum apical membrane antigen 1. Infection and immunity 68 15618180
2014 Immunological markers of Plasmodium vivax exposure and immunity: a systematic review and meta-analysis. BMC medicine 67 25199532
2005 Domain III of Plasmodium falciparum apical membrane antigen 1 binds to the erythrocyte membrane protein Kx. Proceedings of the National Academy of Sciences of the United States of America 67 15805191
2009 Humoral immune response to mixed PfAMA1 alleles; multivalent PfAMA1 vaccines induce broad specificity. PloS one 65 19956619
2001 Multistage multiantigen heterologous prime boost vaccine for Plasmodium knowlesi malaria provides partial protection in rhesus macaques. Infection and immunity 65 11500430
2007 Malaria vaccines: are we getting closer? Current opinion in molecular therapeutics 63 17330398
2009 A randomized and controlled Phase 1 study of the safety and immunogenicity of the AMA1-C1/Alhydrogel + CPG 7909 vaccine for Plasmodium falciparum malaria in semi-immune Malian adults. Vaccine 62 19874925
2026 Extreme Genetic Diversity and Signatures of Balancing Selection in Plasmodium vivax Blood-Stage Antigens. The Journal of infectious diseases 2 41128014
2026 Continental-scale genomic surveillance of Plasmodium falciparum malaria across sub-Saharan Africa with rapid nanopore sequencing. Nature communications 2 42115168
2025 Serology reveals comparable patterns in the transmission intensities of Plasmodium falciparum and Plasmodium vivax in Langkat district, North Sumatera Province, Indonesia. Frontiers in cellular and infection microbiology 2 40034395
2025 Plasmodium falciparum genetic diversity and multiplicity of infection in northern and southern Ghana assessed by amplicon sequencing. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 2 40287078
2026 An abundant merozoite surface protein of Plasmodium falciparum modulates susceptibility to inhibitory antibodies. eLife 1 42504823
2025 A Cryptic Loop that Modulates Protein-Protein Interaction: Implications in PfAMA1-PfRON2 Late-stage Binding Event. Chembiochem : a European journal of chemical biology 1 40067319
2025 Functionality of Toxoplasma gondii antibodies in a population of Beninese pregnant women exposed to malaria. Scientific reports 1 40102442
2025 Immunogenicity of HLA-restricted peptide vaccine candidates delivered by self-assembling protein nanoparticle (SAPN) technology. Vaccine 1 41082812
2026 Genetic polymorphism and natural selection of apical membrane antigen-1 in Plasmodium malariae isolated from Vietnam. BMC infectious diseases 0 41776459
2026 Synthesis and Characterization of Di- and Tetrapropargyl Derivatives of (+)-Catechin: Evaluation of Their Potential Antimalarial Activity Through In Vitro and In Silico Approaches. Chemistry & biodiversity 0 41804297
2026 Cytokine-Driven Immune Phenotypes at Delivery as Indicators of Malaria Infection Among Primigravidae in Burkina Faso: An Exploratory Analysis. Tropical medicine and infectious disease 0 41893415
2026 Distribution of Plasmodium falciparum apical membrane antigen-1 cluster one loop haplotypes and their association with malaria symptoms in Bandiagara, Mali. BMC infectious diseases 0 41923211
2026 Life Course Malaria Exposure and SARS-CoV-2 Seroepidemiology in Ugandan Adolescents: A Longitudinal Study Nested in a Birth Cohort. Tropical medicine & international health : TM & IH 0 42023758
2026 Comparison of techniques and markers to distinguish Plasmodium falciparum recrudescence from new infection in Rwanda. Scientific reports 0 42270857
2026 Structural basis for host membrane binding and remodeling by invading malaria parasites. Cell 0 42379167
2026 Immunodominant B-cell epitopes for precision surveillance of Plasmodium vivax malaria. Emerging microbes & infections 0 42405907
2026 Reconstruction of historical malaria transmission in Senegal using multiplex serocatalytic models. PLoS computational biology 0 42507702
2025 Holding hands to halt malaria: stronger together through heterotypic antibody interactions. Trends in parasitology 0 40268600
2025 Development of high affinity antibodies to Plasmodium falciparum merozoite and sporozoite antigens during infancy and adulthood. Frontiers in immunology 0 40672955
2025 Plasmodium falciparum Liver Stage Antigen 3 plays a role in completing the final stages of merozoite invasion of red blood cells. International journal for parasitology 0 41135800