Crystal structure and collagen-binding site of immune inhibitory receptor LAIR-1: unexpected implications for collagen binding by platelet receptor GPVI.
Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1), one of the most widely spread immune receptors, attenuates immune cell activation when bound to specific sites in collagen. The collagen-binding 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 collagen-binding 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.
Brondijk
T Harma C
TH
Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.
de Ruiter
Talitha
T
Ballering
Joost
J
Wienk
Hans
H
Lebbink
Robert Jan
RJ
van Ingen
Hugo
H
Boelens
Rolf
R
Farndale
Richard W
RW
Meyaard
Linde
L
Huizinga
Eric G
EG
D001665:Binding Sites / Q000502:physiology; D003094:Collagen / Q000378:metabolism*; D003461:Crystallography; D015870:Gene Expression; D006801:Humans; D020014:K562 Cells; D016296:Mutagenesis; D019906:Nuclear Magnetic Resonance, Biomolecular; D015539:Platelet Activation / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship
D010980:Platelet Membrane Glycoproteins; D011971:Receptors, Immunologic; C108073:leukocyte-associated immunoglobulin-like receptor 1; C098341:platelet membrane glycoprotein VI; D003094:Collagen