Structural basis of LAIR1 targeting by polymorphic Plasmodium RIFINs

• Published in: Nature communications Vol. 12; no. 1; pp. 4226 - 8
• Main Authors: Xu, Kai, Wang, Yiran, Shen, Chen-Hsiang, Chen, Yiwei, Zhang, Baoshan, Liu, Kevin, Tsybovsky, Yaroslav, Wang, Shuishu, Farney, S. Katie, Gorman, Jason, Stephens, Tyler, Verardi, Raffaello, Yang, Yongping, Zhou, Tongqing, Chuang, Gwo-Yu, Lanzavecchia, Antonio, Piccoli, Luca, Kwong, Peter D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.07.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/535/1266; 692/699/255/1629; Antibodies; Antibodies, Protozoan - genetics; Antibodies, Protozoan - metabolism; Antigenic Variation - genetics; Antigens; Antigens, Protozoan - immunology; Antigens, Protozoan - metabolism; Antigens, Protozoan - ultrastructure; BASIC BIOLOGICAL SCIENCES; Binding; Crystal structure; Crystallography, X-Ray; Domains; Erythrocytes; Humanities and Social Sciences; Humans; Hydrophobicity; Immune response; Immune system; Inserts; Malaria; Malaria, Falciparum - immunology; Malaria, Falciparum - parasitology; Membrane Proteins - immunology; Membrane Proteins - metabolism; Membrane Proteins - ultrastructure; multidisciplinary; Mutation; Pathogenesis; Plasmodium; Plasmodium falciparum - immunology; Plasmodium falciparum - metabolism; Protein Domains - genetics; Protozoan Proteins - immunology; Protozoan Proteins - metabolism; Protozoan Proteins - ultrastructure; Receptor mechanisms; Receptors; Receptors, Immunologic - immunology; Receptors, Immunologic - metabolism; Receptors, Immunologic - ultrastructure; Science; Science (multidisciplinary); Sequence analysis; Surface antigens; Vector-borne diseases; x-ray crystallography
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24291-6

RIFIN, a large family of Plasmodium variant surface antigens, plays a crucial role in malaria pathogenesis by mediating immune suppression through activation of inhibitory receptors such as LAIR1, and antibodies with LAIR1 inserts have been identified that bind infected erythrocytes through RIFIN. However, details of RIFIN-mediated LAIR1 recognition and receptor activation have been unclear. Here, we use negative-stain EM to define the architecture of LAIR1-inserted antibodies and determine crystal structures of RIFIN-variable 2 (V2) domain in complex with a LAIR1 domain. These structures reveal the LAIR1-binding region of RIFIN to be hydrophobic and membrane-distal, to exhibit extensive structural diversity, and to interact with RIFIN-V2 in a one-to-one fashion. Through structural and sequence analysis of various LAIR1 constructs, we identify essential elements of RIFIN-binding on LAIR1. Furthermore, a structure-derived LAIR1-binding sequence signature ascertained >20 LAIR1-binding RIFINs, including some from P. falciparum field strains and Plasmodium species infecting gorillas and chimpanzees. RIFINs are Plasmodium surface antigens that suppress the immune response by binding inhibitory receptors such as LAIR1. Here, Xu et al . characterize the interaction between RIFIN-variable 2 domain and a LAIR1 domain and identify LAIR1-binding RIFINs in several Plasmodium species.