Crystal Structure of a Fab Complex Formed with PfMSP1-19, the C-terminal Fragment of Merozoite Surface Protein 1 from Plasmodium falciparum: A Malaria Vaccine Candidate

Pizarro, J.C.; Chitarra, V.; Verger, Denis; Holm, Inge; Pêtres, Stéphane; Dartevelle, Sylvie; Nato, Farida; Longacre, Shirley; Bentley, G.A.

doi:10.1016/s0022-2836(03)00376-0

Cited by 89 publications

(113 citation statements)

References 55 publications

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“…The most studied (MSP-1) is a 195 kDa molecule, cleaved enzymatically into 83 kDa, 38 kDa, 30 kDa and 42 kDa fragments; the latter is further processed by a subtilisin (SUB), Ca 2+ -dependent enzymatic process into a 33 kDa fragment (used to bind to spectrin on the cytoplasmic face of RBC, to be released later on the merosomes) and a 19 kDa fragment remaining anchored to Mrz membrane (Pizarro et al, 2003) which contains cHABP 5501 ( 1544 MLNISQHQCVKKQCPQNS 1561 ) in its N-terminal portion ( Figure 2D, dark yellow), this being the only fragment found inside newly infected RBCs.…”

Section: Escape Mechanismmentioning

confidence: 99%

“…(D1) MSP-1 19 kDa fragment (PDB code 1OB1) where cHABP 5501 (in dark yellow) was located; it interacts with band 3. At the side is shown the position where monoclonal antibody G.17.12 interacts with the MSP-1 19 kDa fragment (PDB code 1OB1) (Pizarro et al, 2003). RIGHT panel: The boxes (A2, B2, C2 and D2) give a representation of variability using Shannon's diversity index (in red bars) for each amino acid in the proteins' sequence.…”

Section: Escape Mechanismmentioning

confidence: 99%

“…There are also intercalated hypervariable regions, as occurs with Rh5 cHABPs 36727 ( 201 GKYIAVDAFIKKINET YDKV 220 ) and 36735 ( 361 DEYIHKLILSVKSKN LNKDL 380 ) establishing contact with basigin (Chen, L. et al, 2014), and another such as MSP-1 cHABP 5501 ( 1544 MLNISQHQCVKKQC PQNS 1561 ), having a variable aa in its C-terminus and interacting with the band 3 sequence (Pizarro et al, 2003).…”

Section: Escape Mechanismmentioning

confidence: 99%

“…Regarding the 19 kDa MSP-1-derived fragment, a Fab fragment from mouse G17.12 mAb was obtained that does not inhibit Mrz invasion of RBC nor MSP-1 in X-ray crystallography structure; when it was complexed with the recombinant 19 kDa fragment, it bound cHABP 5501 ( 1544 MLNISQHQCVKKQCPQNS 1561 ) in its C-terminus residues ( Figure 2D), 1553 VKKQ 1556 the last being a relatively polymorphic residue, having only Q/H/K mutations (Pizarro et al, 2003).…”

Section: Monoclonal Antibody (Mab) Reactivitymentioning

confidence: 99%

See 3 more Smart Citations

Far from the Madding Crowd: the Molecular Basis for Immunological Escape ofPlasmodium falciparum

Patarroyo¹,

Aza-Conde²,

Moreno-Vranich³

et al. 2017

Current Issues in Molecular Biology

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Like Thomas Hardy's famous novel Far from the Madding Crowd, Plasmodium falciparum parasites display their most relevant survival structures (proteins) involved in host cell invasion far away from the immune system's susceptible regions, displaying tremendous genetic variability, to attract the immune response and escape immune pressure. The 3D structure localisation of the conserved amino acid sequences of this deadly parasite's most relevant proteins involved in host cell invasion, as well as the location of the highly polymorphic, h i g h l y i m m u n o g e n i c r e g i o n s , c l e a r l y demonstrates that such structures are far apart, sometimes 90° to 180° opposite, thereby rendering the immune response useless. It is also shown here that these conserved, f u n c t i o n a l l y -r e l e v a n t s t r u c t u r e s a r e immunologically silent, since no immune response has been induced.

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Section: Escape Mechanismmentioning

confidence: 99%

Section: Escape Mechanismmentioning

confidence: 99%

Section: Escape Mechanismmentioning

confidence: 99%

Section: Monoclonal Antibody (Mab) Reactivitymentioning

confidence: 99%

See 2 more Smart Citations

Far from the Madding Crowd: the Molecular Basis for Immunological Escape ofPlasmodium falciparum

Patarroyo¹,

Aza-Conde²,

Moreno-Vranich³

et al. 2017

Current Issues in Molecular Biology

View full text Add to dashboard Cite

show abstract

“…The protease hydrolyses a single Leu-Asn bond just Nterminal to the first cysteine of the MSP-1 19 domain. Although this is some 96 residues upstream of the GPI anchor, the compact, inverted U-shaped structure of the two EGF-like modules which make up MSP-1 19 (Morgan et al, 1999;Pizarro et al, 2003) means that the cleavage site is probably spatially close to the membrane. A recent analysis of shedding of P. falciparum apical membrane antigen-1 (PfAMA1) showed that release from the parasite surface is the result of cleavage at a Thr-Ser bond just 29 residues upstream of the TMD (Howell et al, 2003).…”

Section: It's What You Do Not the Way That You Do Itmentioning

confidence: 99%

A new release on life: emerging concepts in proteolysis and parasite invasion

Carruthers

Blackman²

2005

Molecular Microbiology

104

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SummaryCell invasion by apicomplexan pathogens such as the malaria parasite and Toxoplasma is accompanied by extensive proteolysis of zoite surface proteins (ZSPs) required for attachment and penetration. Although there is still little known about the proteases involved, a conceptual framework is emerging for the roles of proteolysis in cell invasion. Primary processing of ZSPs, which includes the trimming of terminal peptides or segmentation into multiple fragments, is proposed to activate these adhesive ligands for tight binding to host receptors. Secondary processing, which occurs during penetration, results in the shedding of ZSPs by one of two mechanistically distinct ways, shaving or capping. Resident surface proteins are typically shaved from the surface whereas adhesive ligands mobilized from intracellular secretory vesicles are capped to the posterior end of the parasite before being shed during the final steps of penetration. Intriguingly, recent studies have revealed that ZSPs can be released either by being cleaved adjacent to the membrane anchor or actually within the membrane itself. Mounting evidence suggests that intramembrane cleavage is catalysed by one or more integral membrane serine proteases of the Rhomboid family and we propose that several malaria adhesive ligands may be potential substrates for these enzymes. We also discuss the evidence that the key reason for ZSP shedding during invasion is to break the connection between parasite surface ligands and host receptors. The sequential proteolytic events associated with invasion by pathogenic protozoa may represent vulnerable pathways for the future development of synergistic anti-protozoal therapies.

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Synthesis, Solution Structure and Immune Recognition of an Epidermal Growth Factor‐Like Domain from Plasmodium falciparum Merozoite Surface Protein‐1

James¹,

Moehle²,

Renard³

et al. 2006

ChemBioChem

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The Plasmodium falciparum merozoite surface protein-1 19 kDa fragment (MSP-1(19)) comprises two closely packed EGF-like domains (EGF=epidermal growth factor), each stabilized by three disulfide bonds. The native conformation of this protein is important for eliciting P. falciparum growth inhibitory antibodies. Here we show that the N-terminal EGF domain alone can be chemically synthesized and efficiently refolded to a native-like state, as shown by its solution structure as determined by NMR spectroscopy. In order to study its immunogenicity, the domain was coupled through its N terminus to a phospholipid and incorporated into reconstituted influenza virus-like particles (virosomes). When used to immunize mice, the peptide-loaded virosomes elicited potent humoral immune responses that were shown by Western blots and immunofluorescence assays to cross-react with native MSP-1 on the surfaces of P. falciparum blood stage parasites. This opens the way for a medicinal chemistry-oriented approach to the study and optimization of the antigenicity of the protein as a potential malaria vaccine candidate, whilst exploiting the immunopotentiating properties of influenza virosomes as a delivery vehicle.

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Crystal Structure of a Fab Complex Formed with PfMSP1-19, the C-terminal Fragment of Merozoite Surface Protein 1 from Plasmodium falciparum: A Malaria Vaccine Candidate

Cited by 89 publications

References 55 publications

Far from the Madding Crowd: the Molecular Basis for Immunological Escape ofPlasmodium falciparum

Far from the Madding Crowd: the Molecular Basis for Immunological Escape ofPlasmodium falciparum

A new release on life: emerging concepts in proteolysis and parasite invasion

Synthesis, Solution Structure and Immune Recognition of an Epidermal Growth Factor‐Like Domain from Plasmodium falciparum Merozoite Surface Protein‐1

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