Crystal structure and collagen-binding site of immune inhibitory receptor LAIR-1: unexpected implications for collagen binding by platelet receptor GPVI

Abstract

Leukocyte-associated immunoglobulinlike receptor-1 (LAIR-1), one of the most widely spread immune receptors, attenuates immune cell activation when bound to specific sites in collagen. The collagenbinding domain of LAIR-1 is homologous to that of glycoprotein VI (GPVI), a collagen receptor crucial for platelet activation. Because LAIR-1 and GPVI also display overlapping collagen-binding specificities, a common structural basis for collagen recognition would appear likely. Therefore, it is crucial to gain insight into the molecular interaction of both receptors with their ligand to prevent unwanted cross-reactions during therapeutic intervention. We determined the crystal structure of LAIR-1 and mapped its collagen-binding site by nuclear magnetic resonance (NMR) titrations and mutagenesis. Our data identify R59, E61, and W109 as key residues for collagen interaction. These residues are strictly conserved in LAIR-1 and GPVI alike; however, they are located outside the previously proposed GPVI collagenbinding site. Our data provide evidence for an unanticipated mechanism of collagen recognition common to LAIR-1 and GPVI. This fundamental insight will contribute to the exploration of specific means of intervention in collagen-induced signaling in immunity and hemostasis. (Blood.

Structural basis of collagen recognition by human osteoclast-associated receptor and design of osteoclastogenesis inhibitors

“…The finding that several of these receptors are able to bind to collagen has led to research exploring whether there is a shared collagen-binding region on these receptors, as seen with the utilization of the D1-D2 hinge region by MHC-binding members (23). An intriguing investigation into the mode of collagen recognition of LAIR-1, through NMR titration experiments, revealed a putative collagen-binding site on the single Ig-like domain of LAIR-1 (15). The conservation of several residues in the same region of GPVI, which binds to a shared motif on collagen, led the authors to hypothesize that GPVI and LAIR-1 may use a conserved region for collagen recognition, a region at odds with a previous model of GPVI collagen binding (15,16).…”

“…An intriguing investigation into the mode of collagen recognition of LAIR-1, through NMR titration experiments, revealed a putative collagen-binding site on the single Ig-like domain of LAIR-1 (15). The conservation of several residues in the same region of GPVI, which binds to a shared motif on collagen, led the authors to hypothesize that GPVI and LAIR-1 may use a conserved region for collagen recognition, a region at odds with a previous model of GPVI collagen binding (15,16). Here we present the crystal structure of an LRC member in complex with a CLP.…”

“…Moreover, receptor activator of nuclear factor-κB ligand (RANKL) differentiation of monocytes to osteoclasts is increased in the presence of collagen-like peptides (CLPs) and can be inhibited by the addition of OSCAR antibodies (9). The description of OSCAR as a collagen-binding receptor of the LRC family places OSCAR with other collagenbinding proteins of this family, including glycoprotein VI (GPVI), leukocyte-associated Ig-like receptor-1 (LAIR-1), and the putative member LILRB4 (9)(10)(11)(12)(13)(14)(15)(16).…”

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

“…LAIR-1 is the main inhibitory receptor that binds collagens ( 39 ), and is abundantly expressed on activated neutrophils. LAIR-1 binds to fi bril-forming collagens and transmembrane collagens, including collagen type IV ( 40 Figure 4. NETosis is regulated by ECM molecules and promotes CD5 + B-cell proliferation through NF-κB activation.…”

Co-expression of the collagen receptors leukocyte-associated immunoglobulin-like receptor-1 and glycoprotein VI on a subset of megakaryoblasts

“…8 This is the only inhibitory receptor described so far that binds collagen and the collagen-binding site in LAIR-1 and GPVI overlaps between the two receptors. [19][20][21] In collaboration with our group, Tomlinson et al showed that when both receptors are ectopically expressed on the same cell, LAIR-1 cross-linking abrogates collagen-induced GPVI-signaling. 22 Co-expression of both receptor types on primary cells would, therefore, potentially affect their responsiveness to collagen.…”