7lr3

Complex of Fab 2/6.14 with domain 3 of P. berghei HAP2

Structural highlights

7lr3 is a 6 chain structure with sequence from Mus musculus and Plasmodium berghei. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.8Å
Ligands:	CSD, EPE, PEG
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HAP2_PLABA During fertilization, required on male gametes for their fusion with female gametes, and for subsequent ookinete formation in the host (PubMed:18367645, PubMed:18403203, PubMed:21209845, PubMed:29212032). Thereby, required for mosquito-mediated transmission to other animals (PubMed:18367645, PubMed:18403203, PubMed:29212032). Probably initiates the fusion of gamete cell membranes by inserting part of its extracellular domain into the cell membrane of a female gamete (PubMed:20080406).^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

HAP2 is a transmembrane gamete fusogen found in multiple eukaryotic kingdoms and is structurally homologous to viral class II fusogens. Studies in Plasmodium have suggested that HAP2 is an attractive target for vaccines that block transmission of malaria. HAP2 has three extracellular domains, arranged in the order D2, D1, and D3. Here, we report monoclonal antibodies against the D3 fragment of Plasmodium berghei HAP2 and crystal structures of D3 in complex with Fab fragments of two of these antibodies, one of which blocks fertilization of Plasmodium berghei in vitro and transmission of malaria in mosquitoes. We also show how this Fab binds the complete HAP2 ectodomain with electron microscopy. The two antibodies cross-react with HAP2 among multiple plasmodial species. Our characterization of the Plasmodium D3 structure, HAP2 ectodomain architecture, and mechanism of inhibition provide insights for the development of a vaccine to block malaria transmission.

Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2.,Feng J, Dong X, DeCosta A, Su Y, Angrisano F, Sala KA, Blagborough AM, Lu C, Springer TA Elife. 2021 Dec 23;10:e74707. doi: 10.7554/eLife.74707. PMID:34939934^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Liu Y, Tewari R, Ning J, Blagborough AM, Garbom S, Pei J, Grishin NV, Steele RE, Sinden RE, Snell WJ, Billker O. The conserved plant sterility gene HAP2 functions after attachment of fusogenic membranes in Chlamydomonas and Plasmodium gametes. Genes Dev. 2008 Apr 15;22(8):1051-68. doi: 10.1101/gad.1656508. Epub 2008 Mar 26. PMID:18367645 doi:https://dx.doi.org/10.1101/gad.1656508
↑ Hirai M, Arai M, Mori T, Miyagishima SY, Kawai S, Kita K, Kuroiwa T, Terenius O, Matsuoka H. Male fertility of malaria parasites is determined by GCS1, a plant-type reproduction factor. Curr Biol. 2008 Apr 22;18(8):607-13. PMID:18403203 doi:10.1016/j.cub.2008.03.045
↑ Mori T, Hirai M, Kuroiwa T, Miyagishima SY. The functional domain of GCS1-based gamete fusion resides in the amino terminus in plant and parasite species. PLoS One. 2010 Dec 31;5(12):e15957. doi: 10.1371/journal.pone.0015957. PMID:21209845 doi:https://dx.doi.org/10.1371/journal.pone.0015957
↑ Angrisano F, Sala KA, Da DF, Liu Y, Pei J, Grishin NV, Snell WJ, Blagborough AM. Targeting the Conserved Fusion Loop of HAP2 Inhibits the Transmission of Plasmodium berghei and falciparum. Cell Rep. 2017 Dec 5;21(10):2868-2878. PMID:29212032 doi:10.1016/j.celrep.2017.11.024
↑ Wong JL, Johnson MA. Is HAP2-GCS1 an ancestral gamete fusogen? Trends Cell Biol. 2010 Mar;20(3):134-41. PMID:20080406 doi:10.1016/j.tcb.2009.12.007
↑ Feng J, Dong X, DeCosta A, Su Y, Angrisano F, Sala KA, Blagborough AM, Lu C, Springer TA. Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2. Elife. 2021 Dec 23;10:e74707. PMID:34939934 doi:10.7554/eLife.74707

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Liu Y, Tewari R, Ning J, Blagborough AM, Garbom S, Pei J, Grishin NV, Steele RE, Sinden RE, Snell WJ, Billker O. The conserved plant sterility gene HAP2 functions after attachment of fusogenic membranes in Chlamydomonas and Plasmodium gametes. Genes Dev. 2008 Apr 15;22(8):1051-68. doi: 10.1101/gad.1656508. Epub 2008 Mar 26. PMID:18367645 doi:https://dx.doi.org/10.1101/gad.1656508

[2] Hirai M, Arai M, Mori T, Miyagishima SY, Kawai S, Kita K, Kuroiwa T, Terenius O, Matsuoka H. Male fertility of malaria parasites is determined by GCS1, a plant-type reproduction factor. Curr Biol. 2008 Apr 22;18(8):607-13. PMID:18403203 doi:10.1016/j.cub.2008.03.045

[3] Mori T, Hirai M, Kuroiwa T, Miyagishima SY. The functional domain of GCS1-based gamete fusion resides in the amino terminus in plant and parasite species. PLoS One. 2010 Dec 31;5(12):e15957. doi: 10.1371/journal.pone.0015957. PMID:21209845 doi:https://dx.doi.org/10.1371/journal.pone.0015957

[4] Angrisano F, Sala KA, Da DF, Liu Y, Pei J, Grishin NV, Snell WJ, Blagborough AM. Targeting the Conserved Fusion Loop of HAP2 Inhibits the Transmission of Plasmodium berghei and falciparum. Cell Rep. 2017 Dec 5;21(10):2868-2878. PMID:29212032 doi:10.1016/j.celrep.2017.11.024

[5] Wong JL, Johnson MA. Is HAP2-GCS1 an ancestral gamete fusogen? Trends Cell Biol. 2010 Mar;20(3):134-41. PMID:20080406 doi:10.1016/j.tcb.2009.12.007

[6] Feng J, Dong X, DeCosta A, Su Y, Angrisano F, Sala KA, Blagborough AM, Lu C, Springer TA. Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2. Elife. 2021 Dec 23;10:e74707. PMID:34939934 doi:10.7554/eLife.74707

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7lr3

Complex of Fab 2/6.14 with domain 3 of P. berghei HAP2

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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