6ZDX

RIFIN variable region bound to LILRB1 ectodomain

Summary for 6ZDX

• Entry DOI: 10.2210/pdb6zdx/pdb
• Descriptor: Rifin, Leukocyte immunoglobulin-like receptor subfamily B member 1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: rifin, lilrb1, inhibitory immune receptor, malaria, infected-erythrocyte, plasmodium falciparum, immune system
• Biological source: Plasmodium falciparum 3D7; More
• Total number of polymer chains: 2
• Total formula weight: 62868.80

Authors

Harrison, T.E.,Higgins, M.K. (deposition date: 2020-06-15, release date: 2020-07-22, Last modification date: 2024-10-23)

Primary citation

Harrison, T.E.,Morch, A.M.,Felce, J.H.,Sakoguchi, A.,Reid, A.J.,Arase, H.,Dustin, M.L.,Higgins, M.K.
Structural basis for RIFIN-mediated activation of LILRB1 in malaria.
Nature, 587:309-312, 2020

PubMed Abstract: The Plasmodium species that cause malaria are obligate intracellular parasites, and disease symptoms occur when these parasites replicate in human blood. Despite the risk of immune detection, the parasite delivers proteins that bind to host receptors on the cell surfaces of infected erythrocytes. In the causative parasite of the most deadly form of malaria in humans, Plasmodium falciparum, RIFINs form the largest family of surface proteins displayed by erythrocytes. Some RIFINs can bind to inhibitory immune receptors, and these RIFINs act as targets for unusual antibodies that contain a LAIR1 ectodomain or as ligands for LILRB1. RIFINs stimulate the activation of and signalling by LILRB1, which could potentially lead to the dampening of human immune responses. Here, to understand how RIFINs activate LILRB1-mediated signalling, we determine the structure of a RIFIN bound to LILRB1. We show that this RIFIN mimics the natural activating ligand of LILRB1, MHC class I, in its LILRB1-binding mode. A single mutation in the RIFIN disrupts the complex, blocks LILRB1 binding of all tested RIFINs and abolishes signalling in a reporter assay. In a supported lipid bilayer system, which mimics the activation of natural killer (NK) cells by antibody-dependent cell-mediated cytotoxicity, both RIFIN and MHC are recruited to the immunological synapse of NK cells and reduce the activation of NK cells, as measured by the mobilization of perforin. Therefore, LILRB1-binding RIFINs mimic the binding mode of the natural ligand of LILRB1 and suppress the function of NK cells.

PubMed: 32650338
DOI: 10.1038/s41586-020-2530-3

Experimental method

X-RAY DIFFRACTION (3 Å)