title: Structural basis for collagen recognition by the immune receptor OSCAR.
abstract: The osteoclast-associated receptor (OSCAR) is a collagen-binding immune receptor with important roles in dendritic cell maturation and activation of inflammatory monocytes as well as in osteoclastogenesis. The crystal structure of the OSCAR ectodomain is presented, both free and in complex with a consensus triple-helical peptide (THP). The structures revealed a collagen-binding site in each immunoglobulin-like domain (D1 and D2). The THP binds near a predicted collagen-binding groove in D1, but a more extensive interaction with D2 is facilitated by the unusually wide D1-D2 interdomain angle in OSCAR. Direct binding assays, combined with site-directed mutagenesis, confirm that the primary collagen-binding site in OSCAR resides in D2, in marked contrast to the related collagen receptors, glycoprotein VI (GPVI) and leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1). Monomeric OSCAR D1D2 binds to the consensus THP with a KD of 28 µM measured in solution, but shows a higher affinity (KD 1.5 μM) when binding to a solid-phase THP, most likely due to an avidity effect. These data suggest a 2-stage model for the interaction of OSCAR with a collagen fibril, with transient, low-affinity interactions initiated by the membrane-distal D1, followed by firm adhesion to the primary binding site in D2.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Long
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Immunobiology, Center for Systems Immunology, and Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Hinerman
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Michal
authors.initials: M
authors.lastname: Blaszczyk
authors.affiliation: Division of Immunobiology, Center for Systems Immunology, and Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.
authors.forename: Jeanette L C
authors.initials: JL
authors.lastname: Miller
authors.affiliation: Division of Immunobiology, Center for Systems Immunology, and Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Conrady
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Barrow
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Dimitri Y
authors.initials: DY
authors.lastname: Chirgadze
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Dominique
authors.initials: D
authors.lastname: Bihan
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Richard W
authors.initials: RW
authors.lastname: Farndale
authors.affiliation: Division of Immunobiology, Center for Systems Immunology, and Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Herr
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003094:Collagen / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism
chemical_list: C512828:OSCAR protein, human; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C108073:leukocyte-associated immunoglobulin-like receptor 1; C098341:platelet membrane glycoprotein VI; D003094:Collagen