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

Ames, James B.; Vyas, Vinay V.; Lusin, Jacqueline D.; Mariuzza, Roy A.

doi:10.1021/bi050139s

Cited by 13 publications

(6 citation statements)

References 38 publications

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“…3C and D). The 3-D structure of 2B4-CD48 complex suggests that the FG-loop of 2B4 is located very close to the CC 0 -loop of CD48 and is involved in the 2B4-CD48 interaction [26,31]. Therefore, the change in the folding and conformation of h2B4-B could potentially alter the receptor-ligand binding resulting in its reduced binding to CD48 observed in our study.…”

Section: H2b4-b Shows Conformational Changes In the Predicted Structurementioning

confidence: 60%

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: H2b4-b Shows Conformational Changes In the Predicted Structurementioning

confidence: 60%

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

et al. 2009

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“…4, A and B) and FG and CCЈ loop conformation (Fig. 2) between rat CD2 and mouse CD244 (16), suggest that the CD244-CD48 interaction may involve substantially different contacts.…”

Section: Figure 4 the Electrostatic Potential Of Cd48-related Proteinsmentioning

confidence: 95%

“…4A) (24) and CD244 (for which only the mouse structure is known, Fig. 4B) (16), but not to the extent of that of human CD2 (Fig. 4C) (25) and CD58 (Fig.…”

Section: Cd48 Mutationmentioning

confidence: 98%

“…CD244 is expressed on NK cells, and a subset of T cells and is involved in triggering the non-major histocompatibility complex-restricted killing of CD48-expressing target cells (11)(12)(13). Two rat homologues of CD244 have been identified (14,15), and the structure of the mouse homologue has been determined using NMR methods (16). Apart from the interaction of human CD2 with CD58 (17), of murine CD48 with CD2 (18) and CD244 (10), and of human SLAM with itself (19), the network of interactions of the CD2 subset of the IgSF is uncharacterized; there is some evidence, however, that, like SLAM, several of the proteins are homophilic (reviewed by Engels et al (1)).…”

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confidence: 99%

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Crystal Structure and Binding Properties of the CD2 and CD244 (2B4)-binding Protein, CD48

Evans

Castro

O’Brien

et al. 2006

Journal of Biological Chemistry

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The structural analysis of surface proteins belonging to the CD2 subset of the immunoglobulin superfamily has yielded important insights into transient cellular interactions. In mice and rats, CD2 and CD244 (2B4), which are expressed predominantly on T cells and natural killer cells, respectively, bind the same, broadly expressed ligand, CD48. Structures of CD2 and CD244 have been solved previously, and we now present the structure of the receptor-binding domain of rat CD48. The receptor-binding surface of CD48 is unusually flat, as in the case of rat CD2, and shares a high degree of electrostatic complementarity with the equivalent surface of CD2. The relatively simple arrangement of charged residues and this flat topology explain why CD48 cross-reacts with CD2 and CD244 and, in rats, with the CD244-related protein, 2B4R. Comparisons of modeled complexes of CD2 and CD48 with the complex of human CD2 and CD58 are suggestive of there being substantial plasticity in the topology of ligand binding by CD2. Thermodynamic analysis of the native CD48-CD2 interaction indicates that binding is driven by equivalent, weak enthalpic and entropic effects, in contrast to the human CD2-CD58 interaction, for which there is a large entropic barrier. Overall, the structural and biophysical comparisons of the CD2 homologues suggest that the evolutionary diversification of interacting cell surface proteins is rapid and constrained only by the requirement that binding remains weak and specific.

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“…Furthermore, the hallmark disulfide bond that links the B and F strands in canonical IgV domains is absent in CD84. Based on sequence analysis, both of these unique features are predicted to be present in all SLAM/CD2 family members and, in fact, have been directly observed in CD2, CD58 (17), 2B4 (18), and NTB-A (12).…”

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confidence: 99%

Structure of CD84 provides insight into SLAM family function

Yan

Malashkevich

Fedorov

et al. 2007

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

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The signaling lymphocyte activation molecule (SLAM) family includes homophilic and heterophilic receptors that modulate both adaptive and innate immune responses. These receptors share a common ectodomain organization: a membrane-proximal immunoglobulin constant domain and a membrane-distal immunoglobulin variable domain that is responsible for ligand recognition. CD84 is a homophilic family member that enhances IFN-␥ secretion in activated T cells. Our solution studies revealed that CD84 strongly self-associates with a Kd in the submicromolar range. These data, in combination with previous reports, demonstrate that the SLAM family homophilic affinities span at least three orders of magnitude and suggest that differences in the affinities may contribute to the distinct signaling behavior exhibited by the individual family members. The 2.0 Å crystal structure of the human CD84 immunoglobulin variable domain revealed an orthogonal homophilic dimer with high similarity to the recently reported homophilic dimer of the SLAM family member NTB-A. Structural and chemical differences in the homophilic interfaces provide a mechanism to prevent the formation of undesired heterodimers among the SLAM family homophilic receptors. These structural data also suggest that, like NTB-A, all SLAM family homophilic dimers adopt a highly kinked organization spanning an end-to-end distance of Ϸ140 Å. This common molecular dimension provides an opportunity for all two-domain SLAM family receptors to colocalize within the immunological synapse and bridge the T cell and antigen-presenting cell.homophilic ͉ dimer ͉ affinity

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

Cited by 13 publications

References 38 publications

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

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

Crystal Structure and Binding Properties of the CD2 and CD244 (2B4)-binding Protein, CD48

Structure of CD84 provides insight into SLAM family function

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

Cited by 13 publications

References 38 publications

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

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

Crystal Structure and Binding Properties of the CD2 and CD244 (2B4)-binding Protein, CD48

Structure of CD84 provides insight into SLAM family function

Contact Info

Product

Resources

About

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