Molecular mechanism of the recognition of bacterially cleaved immunoglobulin by the immune regulatory receptor LILRA2

• Yamazaki Rika

• Furukawa Atsushi

• Hirayasu Kouyuki

• Yumoto Kohei

• Fukuhara Hideo

• Arase Hisashi

• Maenaka Katsumi

• 古川 敦

• 平安 恒幸

Abstract

Human leukocyte immunoglobulin-like receptors (LILRs) typically regulate immune activation by binding to the human leukocyte antigen class I molecules. LILRA2, a member of the LILR family, was recently reported to bind to other unique ligands, the bacterially degraded Igs (N-truncated Igs), for the activation of immune cells. Therefore, LILRA2 is currently attracting significant attention as a novel innate immune receptor. However, the detailed recognition mechanisms required for this interaction remain unclear. In this study, using several biophysical techniques, we uncovered the molecular mechanism of N-truncated Ig recognition by LILRA2. Surface plasmon resonance analysis disclosed that LILRA2 specifically binds to N-truncated Ig with weak affinity (K-d= 4.8 ?m) and fast kinetics. However, immobilized LILRA2 exhibited a significantly enhanced interaction with N-truncated Ig due to avidity effects. This suggests that cell surface-bound LILRA2 rapidly monitors and identifies bi- or multivalent abnormal N-truncated Igs through specific cross-linking to induce immune activation. Van't Hoff analysis revealed that this interaction is enthalpy-driven, with a small entropy loss, and results from differential scanning calorimetry indicated the instability of the putative LILRA2-binding site, the Fab region of the N-truncated Ig. Atomic force microscopy revealed that N truncation does not cause significant structural changes in Ig. Furthermore, mutagenesis analysis identified the hydrophobic region of LILRA2 domain 2 as the N-truncated Ig-binding site, representing a novel ligand-binding site for the LILR family. These results provide detailed insights into the molecular regulation of LILR-mediated immune responses targeting ligands that have been modified by bacteria.

Journal

• Journal of Biological Chemistry

  Journal of Biological Chemistry 295 (28), 9531-9541, 2020-07-10

  American Society for Biochemistry and Molecular Biology Inc.

Keywords

• cell surface receptor
• immunoglobulin G (IgG)
• protein-protein interaction
• surface plasmon resonance (SPR)
• atomic force microscopy (AFM)
• immune regulatory receptor
• bacterially cleaved immunoglobulin
• immune regulation
• leukocyte immunoglobulin-like re

Details

• CRID: 1390293412208784000
• NII Article ID: 120007116484
• NII Book ID: AA00251083
• ISSN: 1083351X
• ISSN: 00219258
• DOI: 10.24517/00067080
• DOI: 10.1074/jbc.ra120.013354
• HANDLE: 2115/82211
• Web Site: http://hdl.handle.net/2297/00067080
• Web Site: https://api.elsevier.com/content/article/PII:S002192581748971X?httpAccept=text/xml
• Web Site: https://api.elsevier.com/content/article/PII:S002192581748971X?httpAccept=text/plain
• Web Site: https://syndication.highwire.org/content/doi/10.1074/jbc.RA120.013354
• Text Lang: en
• Data Source:
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  • CiNii Articles
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