Cryo-EM structure of endogenous Pfs230:Pfs48/45 complex with six antibodies reveals mechanisms of malaria transmission-blocking activity
The Pfs230:Pfs48/45 complex forms the basis for leading malaria transmission-blocking vaccine candidates, yet little is known about its molecular assembly. Here, we used cryo-electron microscopy to elucidate the structure of the endogenous Pfs230:Pfs48/45 complex bound to six transmission-blocking antibodies. Our structure revealed that Pfs230 consists of multiple domain clusters rigidified by interactions mediated through insertion domains. Membrane-anchored Pfs48/45 formed a disk-like structure, interacting with a short C-terminal peptide on Pfs230 that was critical for Pfs230 membrane-retention in vivo. Membrane retention through this interaction was not essential for transmission to mosquitoes, suggesting that complex disruption is not a mode of action for transmission-blocking antibodies. Analyses of Pfs48/45- and Pfs230-targeted antibodies identified conserved epitopes on the Pfs230:Pfs48/45 complex and provided a structural paradigm for complement-dependent activity of Pfs230-targeting antibodies. Altogether, the antibody-bound Pfs230:Pfs48/45 structure improves our molecular understanding of this biological complex, informing the development of next-generation Plasmodium falciparum transmission-blocking interventions.
Authors
- Pascal W.T.C. Jansen (ORCID: https://orcid.org/0000-0003-3064-5742)
- Eizo Takashima (ORCID: https://orcid.org/0000-0001-9070-8499)
- Matthew R. Jackman (ORCID: https://orcid.org/0000-0002-1639-3879)
- Renate C. van Daalen
- Atsushi Maeda
- Taco W. A. Kooij (ORCID: https://orcid.org/0000-0002-8547-7523)
- Sophia Hailemariam (ORCID: https://orcid.org/0000-0002-5999-4244)
- Danton Ivanochko (ORCID: https://orcid.org/0000-0002-2826-8100)
- Nicholas I. Proellochs (ORCID: https://orcid.org/0000-0003-3750-1135)
- Teun Bousema (ORCID: https://orcid.org/0000-0003-2666-094X)
- Rianne Stoter
- John L. Rubinstein (ORCID: https://orcid.org/0000-0003-0566-2209)
- Carolina M. Andrade (ORCID: https://orcid.org/0000-0002-9763-8857)
- Jean‐Philippe Julien (ORCID: https://orcid.org/0000-0001-7602-3995)
- Maartje R. Inklaar (ORCID: https://orcid.org/0000-0002-7707-9357)
- Randy Yoo (ORCID: https://orcid.org/0000-0002-6952-9039)
- Matthijs M. Jore (ORCID: https://orcid.org/0000-0002-0686-370X)
- Ezra T. Bekkering (ORCID: https://orcid.org/0000-0001-5994-8654)
- Takaaki Yuguchi
- Michiel Vermeulen (ORCID: https://orcid.org/0000-0003-0836-6894)
- Geert-Jan van Gemert
- Fabian Heide
- Oscar T. Wanders
Institutions
- Radboud University Nijmegen (NL)
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- Radboud University Medical Center (NL)
- Radboud Institute for Molecular Life Sciences (NL)
- Oncode Institute (NL)
- SickKids Foundation (CA)
- Ehime University (JP)
Publication Details
- Journal
- Immunity
- Published
- 2025-10-10
- DOI
- https://doi.org/10.1016/j.immuni.2025.09.014
- Citations
- 4
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.22