Structural basis of LAIR1 targeting by polymorphic Plasmodium RIFINs

Kai Xu (), Yiran Wang, Chen-Hsiang Shen, Yiwei Chen, Baoshan Zhang, Kevin Liu, Yaroslav Tsybovsky, Shuishu Wang, S. Katie Farney, Jason Gorman, Tyler Stephens, Raffaello Verardi, Yongping Yang, Tongqing Zhou, Gwo-Yu Chuang, Antonio Lanzavecchia, Luca Piccoli and Peter D. Kwong ()
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Kai Xu: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Yiran Wang: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Chen-Hsiang Shen: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Yiwei Chen: Università della Svizzera italiana
Baoshan Zhang: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Kevin Liu: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Yaroslav Tsybovsky: Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research
Shuishu Wang: National Institute of Allergy and Infectious Diseases, National Institutes of Health
S. Katie Farney: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Jason Gorman: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Tyler Stephens: Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research
Raffaello Verardi: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Yongping Yang: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Tongqing Zhou: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Gwo-Yu Chuang: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Antonio Lanzavecchia: Università della Svizzera italiana
Luca Piccoli: Università della Svizzera italiana
Peter D. Kwong: National Institute of Allergy and Infectious Diseases, National Institutes of Health

Nature Communications, 2021, vol. 12, issue 1, 1-8

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24291-6

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