6LFJ

Structural insight into the recognition of pathogen-derived phosphoglycolipids by C-type lectin receptor DCAR.

(2020) J Biol Chem 295: 5807-5817

• PubMed: 32139512 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1074/jbc.RA120.012491
• Primary Citation of Related Structures:  
  6KZR, 6LFJ, 6LKR


• PubMed Abstract: 
  

  The C-type lectin receptors (CLRs) form a family of pattern recognition receptors that recognize numerous pathogens, such as bacteria and fungi, and trigger innate immune responses. The extracellular carbohydrate-recognition domain (CRD) of CLRs forms a globular structure that can coordinate a Ca ²⁺ ion, allowing receptor interactions with sugar-containing ligands. Although well-conserved, the CRD fold can also display differences that directly affect the specificity of the receptors for their ligands. Here, we report crystal structures at 1.8-2.3 Å resolutions of the CRD of murine dendritic cell-immunoactivating receptor (DCAR, or Clec4b1 ), the CLR that binds phosphoglycolipids such as acylated phosphatidyl- myo -inositol mannosides (AcPIMs) of mycobacteria. Using mutagenesis analysis, we identified critical residues, Ala ¹³⁶ and Gln ¹⁹⁸ , on the surface surrounding the ligand-binding site of DCAR, as well as an atypical Ca ²⁺ -binding motif (Glu-Pro-Ser/EPS _168-170 ). By chemically synthesizing a water-soluble ligand analog, inositol-monophosphate dimannose (IPM2), we confirmed the direct interaction of DCAR with the polar moiety of AcPIMs by biolayer interferometry and co-crystallization approaches. We also observed a hydrophobic groove extending from the ligand-binding site that is in a suitable position to interact with the lipid portion of whole AcPIMs. These results suggest that the hydroxyl group-binding ability and hydrophobic groove of DCAR mediate its specific binding to pathogen-derived phosphoglycolipids such as mycobacterial AcPIMs.

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Organizational Affiliation: 

Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan; Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka University, Suita 565-0871, Japan; Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.