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

Reetesh Raj Akhouri,Mats Wahlgren,Suchi Goel,Hirotoshi Furusho,Ulf Skoglund

doi:10.1016/j.celrep.2015.12.067

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.

Highlights

Immunoglobulin M (IgM) is the natural antibody that participates in the first line of defense against invading pathogens and an antibody response that is conserved in all vertebrates (Fellah et al, 1992)
Microvascular binding mediated by P. falciparum erythrocyte membrane protein-1 (PfEMP1) in complex with non-immune immunoglobulin M (IgM) is common among parasites that cause both severe childhood malaria and pregnancy-associated malaria
Three-dimensional reconstructions of IgM reveal that it has a dome-like core, randomly oriented Fab2s units, and the overall shape of a turtle

Summary

Introduction

Immunoglobulin M (IgM) is the natural antibody that participates in the first line of defense against invading pathogens and an antibody response that is conserved in all vertebrates (Fellah et al, 1992). IgM acts as a receptor when expressed on the surface of immune cells, and soluble IgM activates complement pathway to clear pathogens (Ehrenstein and Notley, 2010). Membrane-bound IgM functions as a dimer whereas pentameric form is the functional unit of soluble IgM (Tolar et al, 2009). Soluble pentameric IgM consists of 70 immunoglobulin domains and a J chain that together assemble into pentameric form (Perkins et al, 1991). The Cm4 domain has been shown to oligomerize membrane-bound IgM on B cell surfaces (Tolar et al, 2009)

Results

Discussion

Conclusion