8fg0

Crystal structure of the 3764 Fab in complex with the C-terminal PfCSP linker, PfCSP281-294.Crystal structure of the 3764 Fab in complex with the C-terminal PfCSP linker, PfCSP281-294.

Structural highlights

8fg0 is a 6 chain structure with sequence from Homo sapiens and Plasmodium falciparum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.36Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CSP_PLAF7 Essential sporozoite protein (PubMed:29554084, PubMed:32150583). In the mosquito vector, required for sporozoite development in the oocyst, migration through the vector hemolymph and entry into the vector salivary glands (By similarity). In the vertebrate host, required for sporozoite migration through the host dermis and infection of host hepatocytes (PubMed:29554084, PubMed:32150583). Binds to highly sulfated heparan sulfate proteoglycans (HSPGs) on the surface of host hepatocytes (By similarity).[UniProtKB:P23093]^[1] ^[2] In the vertebrate host, binds to highly sulfated heparan sulfate proteoglycans (HSPGs) on the surface of host hepatocytes and is required for sporozoite invasion of the host hepatocytes.[UniProtKB:P23093]

Publication Abstract from PubMed

Human monoclonal antibodies (mAbs) against the central repeat and junction domain of Plasmodium falciparum circumsporozoite protein (PfCSP) have been studied extensively to guide malaria vaccine design compared to antibodies against the PfCSP C terminus. Here, we describe the molecular characteristics and protective potential of 73 germline and mutated human mAbs against the highly immunogenic PfCSP C-terminal domain. Two mAbs recognized linear epitopes in the C-terminal linker with sequence similarity to repeat and junction motifs, whereas all others targeted conformational epitopes in the alpha-thrombospondin repeat (alpha-TSR) domain. Specificity for the polymorphic Th2R/Th3R but not the conserved RII+/CS.T3 region in the alpha-TSR was associated with IGHV3-21/IGVL3-21 or IGLV3-1 gene usage. Although the C terminus specific mAbs showed signs of more efficient affinity maturation and class-switching compared to anti-repeat mAbs, live sporozoite binding and inhibitory activity was limited to a single C-linker reactive mAb with cross-reactivity to the central repeat and junction. The data provide novel insights in the human anti-C-linker and anti-alpha-TSR antibody response that support exclusion of the PfCSP C terminus from malaria vaccine designs.

Molecular and functional properties of human Plasmodium falciparum CSP C-terminus antibodies.,Oludada OE, Costa G, Burn Aschner C, Obraztsova AS, Prieto K, Canetta C, Hoffman SL, Kremsner PG, Mordmuller B, Murugan R, Julien JP, Levashina EA, Wardemann H EMBO Mol Med. 2023 Jun 7;15(6):e17454. doi: 10.15252/emmm.202317454. Epub 2023 , Apr 21. PMID:37082831^[3]

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

References

↑ Tan J, Sack BK, Oyen D, Zenklusen I, Piccoli L, Barbieri S, Foglierini M, Fregni CS, Marcandalli J, Jongo S, Abdulla S, Perez L, Corradin G, Varani L, Sallusto F, Sim BKL, Hoffman SL, Kappe SHI, Daubenberger C, Wilson IA, Lanzavecchia A. A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein. Nat Med. 2018 Mar 19. pii: nm.4513. doi: 10.1038/nm.4513. PMID:29554084 doi:http://dx.doi.org/10.1038/nm.4513
↑ Oyen D, Torres JL, Aoto PC, Flores-Garcia Y, Binter S, Pholcharee T, Carroll S, Reponen S, Wash R, Liang Q, Lemiale F, Locke E, Bradley A, King CR, Emerling D, Kellam P, Zavala F, Ward AB, Wilson IA. Structure and mechanism of monoclonal antibody binding to the junctional epitope of Plasmodium falciparum circumsporozoite protein. PLoS Pathog. 2020 Mar 9;16(3):e1008373. doi: 10.1371/journal.ppat.1008373. PMID:32150583 doi:http://dx.doi.org/10.1371/journal.ppat.1008373
↑ Oludada OE, Costa G, Burn Aschner C, Obraztsova AS, Prieto K, Canetta C, Hoffman SL, Kremsner PG, Mordmüller B, Murugan R, Julien JP, Levashina EA, Wardemann H. Molecular and functional properties of human Plasmodium falciparum CSP C-terminus antibodies. EMBO Mol Med. 2023 Apr 21:e17454. PMID:37082831 doi:10.15252/emmm.202317454

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OCA

[1] Tan J, Sack BK, Oyen D, Zenklusen I, Piccoli L, Barbieri S, Foglierini M, Fregni CS, Marcandalli J, Jongo S, Abdulla S, Perez L, Corradin G, Varani L, Sallusto F, Sim BKL, Hoffman SL, Kappe SHI, Daubenberger C, Wilson IA, Lanzavecchia A. A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein. Nat Med. 2018 Mar 19. pii: nm.4513. doi: 10.1038/nm.4513. PMID:29554084 doi:http://dx.doi.org/10.1038/nm.4513

[2] Oyen D, Torres JL, Aoto PC, Flores-Garcia Y, Binter S, Pholcharee T, Carroll S, Reponen S, Wash R, Liang Q, Lemiale F, Locke E, Bradley A, King CR, Emerling D, Kellam P, Zavala F, Ward AB, Wilson IA. Structure and mechanism of monoclonal antibody binding to the junctional epitope of Plasmodium falciparum circumsporozoite protein. PLoS Pathog. 2020 Mar 9;16(3):e1008373. doi: 10.1371/journal.ppat.1008373. PMID:32150583 doi:http://dx.doi.org/10.1371/journal.ppat.1008373

[3] Oludada OE, Costa G, Burn Aschner C, Obraztsova AS, Prieto K, Canetta C, Hoffman SL, Kremsner PG, Mordmüller B, Murugan R, Julien JP, Levashina EA, Wardemann H. Molecular and functional properties of human Plasmodium falciparum CSP C-terminus antibodies. EMBO Mol Med. 2023 Apr 21:e17454. PMID:37082831 doi:10.15252/emmm.202317454

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