The structure of a LAIR1-containing human antibody reveals a novel mechanism of antigen recognition

Abstract

Antibodies are critical components of the human adaptive immune system, providing versatile scaffolds to display diverse antigen-binding surfaces. Nevertheless, most antibodies have similar architectures, with the variable immunoglobulin domains of the heavy and light chain each providing three hypervariable loops, which are varied to generate diversity. The recent identification of a novel class of antibody in humans from malaria endemic regions of Africa was therefore surprising as one hypervariable loop contains the entire collagen-binding domain of human LAIR1. Here, we present the structure of the Fab fragment of such an antibody. We show that its antigen-binding site has adopted an architecture that positions LAIR1, while itself being occluded. This therefore represents a novel means of antigen recognition, in which the Fab fragment of an antibody acts as an adaptor, linking a human protein insert with antigen-binding potential to the constant antibody regions which mediate immune cell recruitment.DOI: http://dx.doi.org/10.7554/eLife.27311.001

Breaking the law: unconventional strategies for antibody diversification

“…Mass spectrometry identified the target antigens for LAIR1 as belonging to members of the repetitive interspersed families of polypeptides (RIFIN) family -the largest family of P. falciparum antigens displayed on infected erythrocytes 9 . Furthermore, X-ray crystallography analyses 11 revealed that LAIR1 is well folded and is displayed on the tip of V region in an appropriate configuration for interaction with antigen (FIG. 1A).…”

“…The antigens are presented as shapes in dark blue. Right panels: side and top views of the structural representations of antibody MGD21 with LAIR1 insertion and of the broadly neutralizing HIV-1 antibody 3BNC60 with indel (created using PDB file 5NST 11 , and 3RPI 117 , respectively). The structural models were visualized by UCSF Chimera software package 118 .…”

Structural basis for RIFIN-mediated activation of LILRB1 in malaria

“…In the causative agent of the most deadly human malaria, Plasmodium falciparum, RIFINs form the largest erythrocyte surface protein family 1 . Some RIFINs can bind inhibitory immune receptors, acting as targets for unusual antibodies containing a LAIR1 ectodomain 2 - 4 , or as ligands for LILRB1 5 . RIFINs stimulate LILRB1 activation and signalling5, thereby potentially dampening human immune responses.…”

Lasso-grafting of macrocyclic peptide pharmacophores yields multi-functional proteins

“…However, for peptides whose "active" structure (i.e., target-bound state) assume lasso-like conformation, loop-insertion often allows functional fusion 23,30 . In fact, such "binding-domain insertion" has been found in several natural antibodies where target-binding is mediated by small (~30 residues) to large (~100 residues) domain inserted at the tip of CDR3 loop 31,32 .…”