title: Architecture of Human IgM in Complex with P. falciparum Erythrocyte Membrane Protein 1.
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.
authors.affiliation: Center for Infectious Disease Research (CID), Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Nobels väg 16, Box 280, 171 77 Stockholm, Sweden.
authors.forename: Reetesh Raj
authors.initials: RR
authors.lastname: Akhouri
authors.affiliation: Center for Infectious Disease Research (CID), Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Nobels väg 16, Box 280, 171 77 Stockholm, Sweden.
authors.forename: Suchi
authors.initials: S
authors.lastname: Goel
authors.affiliation: Structural Cellular Biology Unit, Okinawa Institute for Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Furusho
authors.affiliation: Structural Cellular Biology Unit, Okinawa Institute for Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan. Electronic address: ulf.skoglund@oist.jp.
authors.forename: Ulf
authors.initials: U
authors.lastname: Skoglund
authors.affiliation: Center for Infectious Disease Research (CID), Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Nobels väg 16, Box 280, 171 77 Stockholm, Sweden. Electronic address: mats.wahlgren@ki.se.
authors.forename: Mats
authors.initials: M
authors.lastname: Wahlgren
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D007075:Immunoglobulin M / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000737:chemistry*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D007075:Immunoglobulin M; D015800:Protozoan Proteins