Molecular Recognition of Paired Receptors in the Immune System

Kuroki, Kazuhiko; Furukawa, Akinori; Maenaka, Katsumi

doi:10.3389/fmicb.2012.00429

Cited by 50 publications

(49 citation statements)

References 93 publications

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“…In the CLRs, two amino acids harboring long carbonyl side chains separated by a proline in a cis conformation coordinate a Ca 2+ ion, which forms hydrogen bonds with monosaccharides and determines the binding specificity. CLRs have broad recognition abilities toward not only saccharides but also proteins (5,(7)(8)(9). For instance, human NKR-P1 interacts with Lectin-like transcript 1, and some members of the CD94/NKG2 family interact with HLA-E.…”

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confidence: 99%

Structural analysis for glycolipid recognition by the C-type lectins Mincle and MCL

Furukawa

Kamishikiryo

Mori

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Mincle [macrophage inducible Ca2+ -dependent (C-type) lectin; CLEC4E] and MCL (macrophage C-type lectin; CLEC4D) are receptors for the cord factor TDM (trehalose-6,6′-dimycolate), a unique glycolipid of mycobacterial cell-surface components, and activate immune cells to confer adjuvant activity. Although it is known that receptor-TDM interactions require both sugar and lipid moieties of TDM, the mechanisms of glycolipid recognition by Mincle and MCL remain unclear. We here report the crystal structures of Mincle, MCL, and the Mincle-citric acid complex. The structures revealed that these receptors are capable of interacting with sugar in a Ca 2+ -dependent manner, as observed in other C-type lectins. However, Mincle and MCL uniquely possess shallow hydrophobic regions found adjacent to their putative sugar binding sites, which reasonably locate for recognition of fatty acid moieties of glycolipids. Functional studies using mutant receptors as well as glycolipid ligands support this deduced binding mode. These results give insight into the molecular mechanism of glycolipid recognition through C-type lectin receptors, which may provide clues to rational design for effective adjuvants.X-ray crystallography | innate immunity | mycobacteria | pattern-recognition receptors | myeloid cells

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confidence: 99%

Structural analysis for glycolipid recognition by the C-type lectins Mincle and MCL

Furukawa

Kamishikiryo

Mori

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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152

206

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“…It is believed that activating members exhibit lower affinity to ligands than inhibitory members, possibly preventing undesired overactivation of immune responses (2)(3)(4) [e.g., killer cell Ig-like receptors, CD94/NKG2 heterodimers, leukocyte Ig-like receptors, and CD28/CTLA-4 (5)]. Paired Ig-like type 2 receptor (PILR) is a member of a paired receptor family comprising activating and inhibitory members designated "PILRβ" and "PILRα," respectively.…”

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confidence: 99%

Structural basis for simultaneous recognition of anO-glycan and its attached peptide of mucin family by immune receptor PILRα

Kuroki¹,

Wang²,

Ose³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Paired Ig-like type 2 receptor α (PILRα) recognizes a wide range of O-glycosylated mucin and related proteins to regulate broad immune responses. However, the molecular characteristics of these recognitions are largely unknown. Here we show that sialylated O-linked sugar T antigen (sTn) and its attached peptide region are both required for ligand recognition by PILRα. Furthermore, we determined the crystal structures of PILRα and its complex with an sTn and its attached peptide region. The structures show that PILRα exhibits large conformational change to recognize simultaneously both the sTn O-glycan and the compact peptide structure constrained by proline residues. Binding and functional assays support this binding mode. These findings provide significant insight into the binding motif and molecular mechanism (which is distinct from sugar-recognition receptors) by which O-glycosylated mucin proteins with sTn modifications are recognized in the immune system as well as during viral entry.ucin-type O-glycosylation is highly important in physiological events, but it is too complicated to be fully understood because the structures of modified O-linked sugars are basically heterogeneous and are extremely difficult to predict. However, this complexity is beneficial in discriminating cellular conditions. To date, a number of molecules have been shown to recognize O-glycans, which are important in many biological events, including tumorigenesis and immune evasion (1), as well as infectious diseases. Selectins recognize the O-glycan parts of mucin-type glycoproteins on target cell surfaces to regulate the rolling and attachment of lymphocytes in inflammation and in cancer metastasis. However, how O-glycosylated proteins are recognized by specific receptors has remained largely unclear.To regulate function, the immune system has a fine-tuning mechanism using paired receptors families in which members show opposite (activating and inhibitory) signaling even though their cognate ligand recognitions are essentially similar. It is believed that activating members exhibit lower affinity to ligands than inhibitory members, possibly preventing undesired overactivation of immune responses (2-4) [e.g., killer cell Ig-like receptors, CD94/NKG2 heterodimers, leukocyte Ig-like receptors, and CD28/CTLA-4 (5)]. Paired Ig-like type 2 receptor (PILR) is a member of a paired receptor family comprising activating and inhibitory members designated "PILRβ" and "PILRα," respectively. PILRs have one Ig-like domain in the extracellular region, which is responsible for the ligand recognition. Our previous reports showed that PILRs recognize the O-glycosylated mucin proteins, mouse CD99 (6), and PILR-associating neural protein (PANP) (7). A recent study identified two O-glycosylated ligands for PILRs, neuronal differentiation and proliferation factor-1 (NPDC1) and collectin-12 (COLEC12), expanding the PILRrecognizing O-glycosylated ligand family (8). All PILR ligands are mucin or have mucin-like domains in which the heavy O-glycosylation occurs...

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“…45: 1605-1613 Introduction Natural killer (NK) cells are a component of innate immunity, and display cytotoxic activities against tumor cells and virally infected cells [1,2]. The activities of NK cells are precisely regulated by activating and inhibitory signals, through diverse receptors on the cell surface [3][4][5]. These receptors are encoded in two genomic regions, the leukocyte receptor complex (chromosome 19 in human) [6] and the NK gene complex (chromosome 12 in human) [7,8].…”

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Crystal structure of extracellular domain of human lectin‐like transcript 1 (LLT1), the ligand for natural killer receptor‐P1A

et al. 2015

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Emerging evidence has revealed the pivotal roles of C-type lectin-like receptors (CTLRs) in the regulation of a wide range of immune responses. Human natural killer cell receptor-P1A (NKRP1A) is one of the CTLRs and recognizes another CTLR, lectin-like transcript 1 (LLT1) on target cells to control NK, NKT and Th17 cells. The structural basis for the NKRP1A-LLT1 interaction was limitedly understood. Here, we report the crystal structure of the ectodomain of LLT1. The plausible receptor-binding face of the C-type lectin-like domain is flat, and forms an extended β-sheet. The residues of this face are relatively conserved with another CTLR, keratinocyte-associated C-type lectin, which binds to the CTLR member, NKp65. A LLT1-NKRP1A complex model, prepared using the crystal structures of LLT1 and the keratinocyte-associated C-type lectin-NKp65 complex, reasonably satisfies the charge consistency and the conformational complementarity to explain a previous mutagenesis study. Furthermore, crystal packing and analytical ultracentrifugation revealed dimer formation, which supports a complex model. Our results provide structural insights for understanding the binding modes and signal transduction mechanisms, which are likely to be conserved in the CTLR family, and for further rational drug design towards regulating the LLT1 function.Keywords: Cell surface receptor r Crystal structure r C-type lectin-like receptor r Natural killer cell r Protein-protein interactions Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Katsumi Maenaka e-mail: maenaka@pharm.hokudai.ac.jp * Equal contribution.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 1606 S. Kita et al. Eur. J. Immunol. 2015. 45: 1605-1613 Introduction Natural killer (NK) cells are a component of innate immunity, and display cytotoxic activities against tumor cells and virally infected cells [1,2]. The activities of NK cells are precisely regulated by activating and inhibitory signals, through diverse receptors on the cell surface [3][4][5]. These receptors are encoded in two genomic regions, the leukocyte receptor complex (chromosome 19 in human) [6] and the NK gene complex (chromosome 12 in human) [7,8]. The leukocyte receptor complex encodes the NK receptors of the immunoglobulin (Ig) superfamily, such as killer Ig-like receptors and leukocyte Ig-like receptors, whereas the NK gene complex region encodes the NK receptors of the C-type lectinlike receptors (CTLRs). The CTLRs are subdivided into two groups, according to their expression patterns. Killer cell lectin-like receptors (KLRs) are expressed in NK cells, and C-type lectin receptors (CLECs) are expressed in non-NK cells [9]. The ligands of KLRs are (1) major histocompatibility complex (MHC) class I molecules and relatives, and (2) CLECs. The former members include CD94, the NKG2 subfamily [10], and the Ly49 subfamily [11], and the latter members are the NK receptor-P1 (NKRP1) subfamily [12,13]. The NKRP1 su...

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Molecular Recognition of Paired Receptors in the Immune System

Cited by 50 publications

References 93 publications

Structural analysis for glycolipid recognition by the C-type lectins Mincle and MCL

Structural analysis for glycolipid recognition by the C-type lectins Mincle and MCL

Structural basis for simultaneous recognition of anO-glycan and its attached peptide of mucin family by immune receptor PILRα

Crystal structure of extracellular domain of human lectin‐like transcript 1 (LLT1), the ligand for natural killer receptor‐P1A

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