Architecture of Human IgM in Complex with P. falciparum Erythrocyte Membrane Protein 1

Cell Reports
Reetesh Raj AkhouriM Wahlgren

Abstract

Plasmodium falciparum virulence is associated with sequestration of infected erythrocytes. Microvascular binding mediated by PfEMP1 in complex with non-immune immunoglobulin M (IgM) is common among parasites that cause both severe childhood malaria and pregnancy-associated malaria. Here, we present cryo-molecular electron tomography structures of human IgM, PfEMP1 and their complex. Three-dimensional reconstructions of IgM reveal that it has a dome-like core, randomly oriented Fab2s units, and the overall shape of a turtle. PfEMP1 is a C- shaped molecule with a flexible N terminus followed by an arc-shaped backbone and a bulky C terminus that interacts with IgM. Our data demonstrate that the PfEMP1 binding pockets on IgM overlap with those of C1q, and the bulkiness of PfEMP1 limits the capacity of IgM to interact with PfEMP1. We suggest that P. falciparum exploits IgM to cluster PfEMP1 into an organized matrix to augment its affinity to host cell receptors.

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Citations

Jan 28, 2017·Immunotherapy·Manuel E PatarroyoJorge Aza-Conde
Jun 13, 2017·Nature Reviews. Microbiology·Mats WahlgrenReetesh R Akhouri
Nov 6, 2018·Soft Matter·Anil K Dasanna, Ulrich S Schwarz
Sep 19, 2019·Proceedings of the National Academy of Sciences of the United States of America·Frank LennartzMatthew K Higgins
Sep 27, 2019·Immunological Reviews·Liriye KurtovicJames G Beeson
Jun 4, 2020·Vaccines·Wolfgang W LeitnerElke S Bergmann-Leitner
Mar 18, 2020·FEBS Letters·Patience Kerubo KiyukaAyman Khattab
Jul 19, 2019·Frontiers in Immunology·Wenn-Chyau LeeLaurent Rénia
Jan 17, 2021·Nature Microbiology·Rui MaNiraj H Tolia
Oct 12, 2019·Journal of Pharmaceutical Sciences·Brandon M Hoover, Regina M Murphy
May 27, 2021·Proceedings of the National Academy of Sciences of the United States of America·Yvonne AzasiLouis H Miller
Jun 18, 2021·PloS One·Jun-Hong Ch'ngMats Wahlgren
Jun 26, 2021·Frontiers in Immunology·Dilini RathnayakeStephen J Rogerson
Nov 7, 2017·Cell Host & Microbe·Anne KesslerKami Kim

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