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A Single Residue, Arginine 65, Is Critical for the Functional Interaction of Leukocyte-Associated Inhibitory Receptor-1 with Collagens¹

Xiaobin Tang^*, Sriram Narayanan^*, Giovanna Peruzzi^*, Akintomide Apara^*, Kannan Natarajan, David H. Margulies, John E. Coligan^2,* and Francisco Borrego^2,3,*

^* Receptor Cell Biology Section, Laboratory of Immunogenetics, and Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

ITIM-containing receptors play an essential role in modulating immune responses. Leukocyte-associated inhibitory receptor (LAIR)-1, also known as CD305, is an ITIM-containing inhibitory receptor, expressed by all leukocytes, that binds collagens. In this article, we investigate the effect of a conservative R65K mutation on LAIR-1 ligand binding and function. Compared with LAIR-1 wild-type (wt)-expressing cells, LAIR-1 R65K cells show markedly reduced binding to collagen, which correlates with a reduced level of LAIR-1 polarization to the site of interaction with collagens. Both LAIR-1 wt and R65K cells can generate intracellular signals when ligated by anti-LAIR-1 mAb, but only LAIR-1 wt cells respond to collagens or matrigel. In agreement, surface plasmon resonance analyses showed that LAIR-1 R65K protein has markedly reduced avidity for collagen type I compared with LAIR-1 wt. Likewise, LAIR-1 R65K protein has decreased avidity for cells expressing transmembrane collagen XVII. Thus, a single residue, Arg65, is critical for the interaction of LAIR-1 with collagens.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the intramural program of the National Institute of Allergy and Infectious Diseases.

² J.E.C. and F.B. are cosenior authors and contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Francisco Borrego at the current address: Laboratory of Molecular and Developmental Immunology, Division of Monoclonal Antibodies HFD-123, CDER/FDA, 29 Lincoln Drive, Building 29B, Room 3NN18, Bethesda, MD 20892. E-mail address: Francisco.Borrego{at}fda.hhs.gov

⁴ Abbreviations used in this paper: SHP, Src homology 2 domain-containing protein tyrosine phosphatase; DDR, discoidin domain receptor; GPO, glycine-proline-hydroxyproline; GPVI, glycoprotein VI; LAIR, leukocyte-associated inhibitory receptor; MPI, mean pixel intensity; RU, resonance units; SPR, surface plasmon resonance; wt, wild type.

⁵ The online version of this article contains supplemental material.