Structural basis of LAIR1 targeting by polymorphic Plasmodium RIFINs

Area of Science:

• Malariology
• Immunology
• Structural Biology

Background:

• RIFIN proteins are key Plasmodium falciparum variant surface antigens involved in malaria pathogenesis.
• RIFIN mediates immune suppression by activating inhibitory receptors like LAIR1.
• Previous understanding of RIFIN-LAIR1 recognition and activation mechanisms was limited.

Purpose of the Study:

• To elucidate the structural basis of RIFIN-mediated LAIR1 recognition and activation.
• To define the architecture of LAIR1-inserted antibodies binding to RIFIN.
• To identify essential structural elements for RIFIN-LAIR1 interaction.

Main Methods:

• Negative-stain electron microscopy (EM) to determine antibody architecture.
• X-ray crystallography to solve structures of RIFIN-V2 domain complexed with LAIR1.
• Structural and sequence analysis of RIFIN and LAIR1 constructs.

Main Results:

• The LAIR1-binding region of RIFIN is hydrophobic, membrane-distal, and structurally diverse.
• RIFIN-V2 interacts with LAIR1 in a one-to-one stoichiometric manner.
• Essential RIFIN-binding elements on LAIR1 were identified.
• A sequence signature identified over 20 RIFINs that bind LAIR1, including those from field strains and other Plasmodium species.

Conclusions:

• Structural insights into RIFIN-LAIR1 interaction provide a basis for understanding immune evasion in malaria.
• The identified RIFIN-LAIR1 binding signature aids in discovering new RIFIN variants across Plasmodium species.
• This work contributes to understanding malaria pathogenesis and potential therapeutic targets.