Structure of a Heterophilic Adhesion Complex between the Human CD2 and CD58 (LFA-3) Counterreceptors

Wang, Jia-Huai; Smolyar, Alex; Tan, Kemin; Liu, Jin-huan; Kim, Mi-Kyung; Sun, Zhenyu; Wagner, Gerhard; Reinherz, Ellis L.

doi:10.1016/s0092-8674(00)80790-4

Cited by 222 publications

(245 citation statements)

References 84 publications

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“…This association mode shows overall similarities to that observed in the CD2-CD58 heterophilic complex [33], but it differs in the detailed architecture and physicochemical properties of the interface. Most of the contacting residues in the 2B4-CD48 heterophilic interface are located in loops, whereas the NTB-A homophilic interface is composed mainly of strand-tostrand contacts.…”

Section: Discussionsupporting

confidence: 55%

Functional role of human NK cell receptor 2B4 (CD244) isoforms

et al. 2009

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TX, USA2B4 (CD244), a member of the signaling lymphocyte-activation molecule (SLAM/CD150), is expressed on all NK cells, a subpopulation of T cells, monocytes and basophils. Human NK cells express two isoforms of 2B4, h2B4-A and h2B4-B that differ in a small portion of the extracellular domain. In the present investigation, we have studied the functions of h2B4-A and h2B4-B. Our study demonstrated that these two isoforms differ in their binding affinity for CD48, which results in differential cytotoxic activity as well as intracellular calcium release by NK cells upon target cell recognition. Analysis of the predicted 3-D structure of the two isoforms showed conformational differences that could account for their differences in binding affinity to CD48. h2B4-A was able to mediate natural cytotoxicity against CD48-expressing K562 target cells and induce intracellular calcium release, whereas h2B4-B showed no effects. NK-92MI, U937, THP-1, KU812, primary monocytes, basophils and NK cells showed expression of both h2B4-A and h2B4-B whereas YT and IL-2-activated NK cells did not show any h2B4-B expression. Stimulation of NK cells through 2B4 resulted in decreased mRNA levels of both h2B4-A and h2B4-B indicating that down-regulation of 2B4 isoforms may be an important factor in controlling NK cell activation during immune responses.Key words: Cell activation . Cell surface molecules . NK cells Introduction NK cells are a fundamental component of the innate immune system, capable of recognizing and destroying tumor cells as well as cells that have been infected by viruses or bacteria [1]. In addition to their role in innate immune responses, interactions between NK cells and dendritic cells regulate the adaptive immune response to pathogens [2]. NK cell functions are regulated by a dynamic interplay between activating and inhibitory signals transmitted by distinct classes of receptors found on their surface [3,4]. The balance between positivesignaling receptors and negative-signaling receptors ultimately determines the outcome of NK cell-target cell encounters [5,6].2B4 (CD244), belongs to the signaling lymphocyte-activation molecule (SLAM) family of receptors, which includes SLAM (CD150), CD84, NTB-A (Ly-108), lymphocyte antigen 9 (Ly9; CD229), and CD2-subset 1 (CS1) (also termed CRACC or CD319) [7][8][9][10]. 2B4 is expressed by all NK cells, as well as a subset of memory CD8 1 abT cells, gdT cells, basophils, monocytes and eosinophils [11][12][13][14][15]. 2B4 binds to the glycophosphoinositol anchored protein, CD48, expressed on all hematopoietic cells, with a similar affinity in mouse and human [16,17]. Engagement of 2B4 via interaction with specific antibodies or CD48 induces cytokine secretion (IFN-g) and enhances non-MHC-restricted 1632killing by NK cells [12,16,18]. 2B4 can also function as a ligand on target cells and stimulate NK cells through the engagement of CD48 [19]. 2B4 was initially identified as an activating receptor in non-MHC-restricted killing of NK and T cells [12,20]. Some studies with human ...

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Section: Discussionsupporting

confidence: 55%

Functional role of human NK cell receptor 2B4 (CD244) isoforms

et al. 2009

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“…It also resembles these interactions in that both receptor and ligand are relatively closely related to each other, are located on a small region of the chromosome and are likely to have arisen by gene duplication and evolved from a homophilic interaction [3]. At the molecular level, the finding that CD200 and CD200R interact through the GFCC' faces of their N-terminal domains is similar to the CD2/CD58 interaction [22] and the junctional adhesion molecule-1 (JAM1) homotypic interaction [23]. This face seems to be particularly suited to interactions between cell surface proteins.…”

Section: Discussionmentioning

confidence: 91%

The CD200 and CD200 receptor cell surface proteins interact through their N‐terminal immunoglobulin‐like domains

Hatherley

Barclay

2004

Eur J Immunol

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CD200 (OX2) is a broadly distributed cell surface glycoprotein that interacts with a receptor on myeloid cells (CD200R) involved in regulation of macrophage function. Both CD200 and CD200R contain two Ig superfamily domains like many other leukocyte membrane proteins. Site‐directed mutagenesis of CD200R showed that, like CD200, it interacted through its N‐terminal domain. This indicated that the cell‐cell interaction spans four Ig superfamily domains and this distance is similar to many interactions found between T cells and antigen‐presenting cells. This suggests that this topology is also important in interactions of CD200 on a variety of cells with CD200R on myeloid cells, and comparable contact sites may be important mediating regulation in other cell‐cell interactions. The mutagenesis showed that the binding involved the predicted GFCC′ face of its N‐terminal domain, like that of CD200, suggesting that the interaction evolved from a homotypic interaction.

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“…Preliminary NMR relaxation analysis of the FGloop suggested significant internal dynamics on the subnanosecond time scale (data not shown), consistent with a highly disordered main chain. Interestingly, this long and unstructured FG-loop contains residues that are believed to play a role in ligand binding based on the closely related crystal structure of the CD2-CD58 complex (36). Strands C and C' form a hairpin β-structure connected by a well-defined CC'-loop (residues 37-42) that might also play a role in ligand binding (32,36).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, this long and unstructured FG-loop contains residues that are believed to play a role in ligand binding based on the closely related crystal structure of the CD2-CD58 complex (36). Strands C and C' form a hairpin β-structure connected by a well-defined CC'-loop (residues 37-42) that might also play a role in ligand binding (32,36). Strand C' is interrupted by a β-bulge at Glu45 and Ile46, forming two shorter strands, C 1 ' and C 2 ' (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…The D1 domain of CD48 is ∼28% identical (45% homologous) in primary sequence to that of CD58 ( Figure 1A) whose three-dimensional structure is known (36,37). An approximate three-dimensional structure of the D1 domain of CD48 was calculated by homology modeling based on the known structure of CD58 using the InsightII/Discover/ Homology program (BIOSYM Technology, San Diego, CA).…”

Section: Implications For Ligand Recognitionmentioning

confidence: 99%

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NMR Structure of the Natural Killer Cell Receptor 2B4 (CD244): Implications for Ligand Recognition^,

et al. 2005

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Abstract2B4, a transmembrane receptor expressed primarily on natural killer (NK) cells and on a subset of CD8 + T cells, plays an important role in activating NK-mediated cytotoxicity through its interaction with CD48 on target cells. We report here the atomic-resolution structure of the ligand-binding (D1) domain of 2B4 in solution determined by nuclear magnetic resonance (NMR) spectroscopy. The overall main chain structure resembles an immunoglobulin variable (V) domain fold, very similar to that seen previously for domain 1 of CD2 and CD4. The structure contains nine β-strands assembled into two β-sheets conventionally labeled DEB and AGFCC'C". The six-stranded sheet (AGFCC'C") contains structural features that may have implications for ligand recognition and receptor function. A noncanonical disulfide bridge between Cys2 and Cys99 stabilizes a long and parallel β-structure between strand A (residues 3-12) and strand G (residues 100-108). A β-bulge at residues Glu45 and Ile46 places a bend in the middle of strand C' that orients two conserved and adjacent hydrophobic residues (Ile46 and Leu47) inside the β-sandwich as seen in other V domains. Finally, the FG-loop (implicated in ligand recognition in the CD2-CD58 complex) is dynamically disordered in 2B4 in the absence of a ligand. We propose that ligand binding to 2B4 might stabilize the structure of the FG-loop in the ligand complex.Natural killer (NK) 1 cells are a fundamental component of the innate immune system that play a vital role in the detection and destruction of virally infected and tumor cells (1,2). The cytolytic activity of NK cells is regulated by a dynamic interplay between activating and inhibitory signals transmitted by distinct classes of receptors found on their surface. The dominant signal received by an NK cell through its interaction with normal levels of major histocompatibility complex (MHC) class I on target cells is inhibitory. When expression of MHC class I is reduced through infectious or tumorigenic processes, this inhibitory signal is attenuated, and the NK cell is activated. In this way, cells with abnormal MHC class I expression become targets of NK lytic activity that results from loss of inhibition of NK cell activation. Inhibitory receptors specific for MHC class I include the killer immunoglobulinlike receptors (KIRs), members of the Ly49 family, and the CD94/NKG2D family (3). Activating receptors include 2B4, CD16, CD44, CD69, NKR-P1, NKp30, NKp44, and NKp46 (1,2). However, only for some of these stimulatory receptors are the physiological ligands known: CD48 for 2B4 (4), IgG Fc for CD16 (5), and Clr for NKR-P1 (6). The balance between positive signaling receptors (resulting in target cell lysis) and negative signaling receptors (preventing lysis) ultimately determines the outcome of NK cell-target cell encounters (1,2 EXPERIMENTAL PROCEDURES Protein Expression and PurificationA DNA fragment encoding the ligand-binding domain of rat 2B4 (residues 1-112, referred to throughout the text as simply 2B4) was generated by PCR...

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Structure of a Heterophilic Adhesion Complex between the Human CD2 and CD58 (LFA-3) Counterreceptors

Cited by 222 publications

References 84 publications

Functional role of human NK cell receptor 2B4 (CD244) isoforms

Functional role of human NK cell receptor 2B4 (CD244) isoforms

The CD200 and CD200 receptor cell surface proteins interact through their N‐terminal immunoglobulin‐like domains

NMR Structure of the Natural Killer Cell Receptor 2B4 (CD244): Implications for Ligand Recognition^,

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Structure of a Heterophilic Adhesion Complex between the Human CD2 and CD58 (LFA-3) Counterreceptors

Cited by 222 publications

References 84 publications

Functional role of human NK cell receptor 2B4 (CD244) isoforms

Functional role of human NK cell receptor 2B4 (CD244) isoforms

The CD200 and CD200 receptor cell surface proteins interact through their N‐terminal immunoglobulin‐like domains

NMR Structure of the Natural Killer Cell Receptor 2B4 (CD244): Implications for Ligand Recognition,

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NMR Structure of the Natural Killer Cell Receptor 2B4 (CD244): Implications for Ligand Recognition^,