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8dyx

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Cryo-EM structure of 311 Fab in complex with recombinant shortened Plasmodium falciparum circumsporozoite protein (rsCSP)

Structural highlights

8dyx is a 23 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:	Electron Microscopy, Resolution 3Å
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

The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to PfCSP and in protection from Pf malaria infection. Together, these data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3-33 antibodies and highlight key features underlying the potent protection of this antibody family.

Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection.,Martin GM, Torres JL, Pholcharee T, Oyen D, Flores-Garcia Y, Gibson G, Moskovitz R, Beutler N, Jung DD, Copps J, Lee WH, Gonzalez-Paez G, Emerling D, MacGill RS, Locke E, King CR, Zavala F, Wilson IA, Ward AB Nat Commun. 2023 Jul 28;14(1):4546. doi: 10.1038/s41467-023-40151-x. PMID:37507365^[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
↑ Martin GM, Torres JL, Pholcharee T, Oyen D, Flores-Garcia Y, Gibson G, Moskovitz R, Beutler N, Jung DD, Copps J, Lee WH, Gonzalez-Paez G, Emerling D, MacGill RS, Locke E, King CR, Zavala F, Wilson IA, Ward AB. Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection. Nat Commun. 2023 Jul 28;14(1):4546. PMID:37507365 doi:10.1038/s41467-023-40151-x