Assembly and expression of a synthetic gene encoding the antigen Pfs48/45 of the human malaria parasite Plasmodium falciparum in yeast

Milek, Richard L.B.; Stunnenberg, Hendrik G.; Konings, Ruud N. H.

doi:10.1016/s0264-410x(99)00392-8

Cited by 40 publications

(29 citation statements)

References 38 publications

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“…To date, no experimentally determined molecular structure for any s48/45 domain has been reported, mainly because of proteinexpression challenges (29)(30)(31)(32)(33)(34). However, considering the importance of structural information in the effective design of subunit vaccine candidates, we present the solution three-dimensional structure of the s48/45 domain obtained by NMR spectroscopy of the C-terminal domain of Pf12 expressed in Escherichia coli.…”

mentioning

confidence: 99%

Structure of thePlasmodium6-cysteine s48/45 domain

Arredondo

Cai²,

Takayama³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

107

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The s48/45 domain was first noted in Plasmodium proteins more than 15 y ago. Previously believed to be unique to Plasmodium , the s48/45 domain is present in other aconoidasidans. In Plasmodium , members of the s48/45 family of proteins are localized on the surface of the parasite in different stages, mostly by glycosylphosphatydylinositol-anchoring. Members such as P52 and P36 seem to play a role in invasion of hepatocytes, and Pfs230 and Pfs48/45 are involved in fertilization in the sexual stages and have been consistently studied as targets of transmission-blocking vaccines for years. In this report, we present the molecular structure for the s48/45 domain corresponding to the C-terminal domain of the blood-stage protein Pf12 from Plasmodium falciparum , obtained by NMR. Our results indicate that this domain is a β-sandwich formed by two sheets with a mixture of parallel and antiparallel strands. Of the six conserved cysteines, two pairs link the β-sheets by two disulfide bonds, and the third pair forms a bond outside the core. The structure of the s48/45 domain conforms well to the previously defined surface antigen 1 (SAG1)-related-sequence (SRS) fold observed in the SAG family of surface antigens found in Toxoplasma gondii . Despite extreme sequence divergence, remarkable spatial conservation of one of the disulfide bonds is observed, supporting the hypothesis that the domains have evolved from a common ancestor. Furthermore, a homologous domain is present in ephrins, raising the possibility that the precursor of the s48/45 and SRS domains emerged from an ancient transfer to Apicomplexa from metazoan hosts.

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mentioning

confidence: 99%

Structure of thePlasmodium6-cysteine s48/45 domain

Arredondo

Cai²,

Takayama³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

107

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“…Neither the predicted disulfidebonding patterns in the Ps230 family of proteins nor their structural organization as double domains have yet been confirmed, or contradicted, by direct experimental data. Attempts to express and purify these proteins with conformational integrity have met with limited success (14,15).…”

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confidence: 99%

Structural models for the protein family characterized by gamete surface protein Pfs230 ofPlasmodium falciparum

Gerloff

Creasey

Maslau

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

122

180

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Ps230 is the largest representative of a 10-member family of proteins found in all Plasmodium species. The family is defined by partially conserved, cysteine-rich double domains that are Ϸ350 aa in length and have one to three predicted disulfide bridges in each half. In Plasmodium falciparum, the most dangerous human malaria, Pf12 is the smallest member of the family, comprising just one double domain. Pfs230, with 7 double domains, and Pfs48͞45 and Pfs47, with 1.5 double domains each, are found on the gamete surfaces and are thus potential candidates for a transmissionblocking vaccine. Fold prediction analyses of the double domains in Pfs230 reveal structural resemblance to SAG1 (surface antigen 1), a surface protein with a double ␤-sandwich structure from another apicomplexan parasite, Toxoplasma gondii. Template-directed modeling onto SAG1 clearly establishes the structural link between SAG1 and Pfs230 and produces positions for the cysteines that accord with the disulfide-bonding arrangement predicted for the Pfs230 family in earlier work. A highly clustered region of polymorphisms within the second double domain in Pfs230 maps to one side of the sandwich surface. This observation suggests that this region may be functional and reinforces the validity of these molecular models for the core domains of the Pfs230 family of proteins.malaria ͉ protein structure prediction ͉ fertilization ͉ fold recognition ͉ transmission-blocking vaccine target

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“…The Pfs48/45 gene encodes a unique protein that migrates as a double band under non-reducing conditions (Milek et al 2000). This protein is expressed on P. falciparum gametocyte and gamete surfaces and has a central role in male gamete fertility (van Dijk et al 2001).…”

Section: P Falciparum-derived Tbv Candidate -Pfs48/45mentioning

confidence: 99%

“…In addition to identifying TBV candidates that are effective and may span different insect vector species, studies on TBV development must include antigenic variability present in field isolates (Kocken et al 1995;Drakeley et al 1996;Duffy & Kaslow 1997;Sattabongkot et al 2003), immunogenicity of such antigens (Kubler-Kielb et al 2007), reactogenicity caused by adjuvants (Saul et al 2007;Wu et al 2008), non-specific responses (Quakyi et al 1987;Tonui et al 2001a), and improper folding of antigens (Kaslow et al 1994;Milek et al 1998a;Milek et al 1998b;Milek et al 2000). Natural antigenic boosting is another important issue that must be dealt with (Arevalo-Herrera et al 2005).…”

Section: Future Of Tbvsmentioning

confidence: 99%