NTB-A Receptor Crystal Structure: Insights into Homophilic Interactions in the Signaling Lymphocytic Activation Molecule Receptor Family

Cao, Erhu; Ramagopal, U.A.; Fedorov, A.A.; Fedorov, E.V.; Yan, Qingrong; Lary, Jeffrey W.; Cole, James L.; Nathenson, Stanley G.; Almo, Steven C.

doi:10.1016/j.immuni.2006.06.020

Cited by 66 publications

(59 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7). The CD84 head-to-tail dimer exhibited the same twofold symmetrical organization recently reported for the full NTB-A ectodomain and, most important, is consistent with the formation of an intercellular (T cell-APC) homophilic dimer that can support signaling (see below) (12).…”

Section: Discussionsupporting

confidence: 81%

“…In combination with previously published work (12,13), the current study demonstrated that the homophilic affinities span at least three orders of magnitude. This finding suggested that differences in affinities might be a contributor to the different signaling behavior exhibited by the individual family members.…”

supporting

confidence: 87%

“…The homophilic affinity is in contrast to the NTB-A and CD150 homophilic interactions, which are characterized by K d of 2 M and 200 M, respectively (12,13). The three orders of magnitude range in homophilic affinities suggest a mechanistic basis for the overlapping, but distinct, biological functions exhibited by the SLAM family members.…”

Section: Discussionmentioning

confidence: 99%

“…The CD84 homophilic interaction exhibited significant overall similarity with the recently published NTB-A homophilic dimer. Notably, the physical and chemical properties of the surfaces contributing to the dimer interfaces provide a potential mechanism to prevent unwanted heterodimerization (12). The NTB-A and CD84 crystal structures provide models for other homophilic interactions in the SLAM family.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Structure of CD84 provides insight into SLAM family function

Yan

Malashkevich

Fedorov

et al. 2007

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

Self Cite

View full text Add to dashboard Cite

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

show abstract

Section: Discussionsupporting

confidence: 81%

supporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Structure of CD84 provides insight into SLAM family function

Yan

Malashkevich

Fedorov

et al. 2007

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…NTB-A molecules, the human Ly108 homolog, form homodimers in solution with an equilibrium dissociation constant of ∼2 mM (14). Whereas this modest affinity would not allow Ly108 to mediate cell-cell adhesion, prolonged membrane juxtaposition in the absence of TCR or SAP-dependent signal transduction can drive Ly108 into the interface of cell couples, likely because of the reduced diffusibility after trans engagement.…”

Section: Discussionmentioning

confidence: 99%

SAP-Regulated T Cell–APC Adhesion and Ligation-Dependent and -Independent Ly108–CD3ζ Interactions

Chu

Wang

Zhang

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

The germinal center response requires cooperation between Ag-specific T and B lymphocytes, which takes the form of long-lasting cell–cell conjugation in vivo. Signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) is required for stable cognate T–B cell conjugation, whereas SLAM family transmembrane (TM) receptor Ly108 may negatively regulate this process. We show that, other than phosphotyrosine-binding, SAP does not harbor motifs that recruit additional signaling intermediates to stabilize T–B adhesion. Ly108 dampens T cell adhesion to not only Ag-presenting B cells, but also dendritic cells by inhibiting CD3ζ phosphorylation through two levels of regulated Ly108–CD3ζ interactions. Constitutively associated with Src homology 2 domain–containing tyrosine phosphatase-1 even in SAP-competent cells, Ly108 is codistributed with the CD3 complex within a length scale of 100–200 nm on quiescent cells and can reduce CD3ζ phosphorylation in the absence of overt TCR stimulation or Ly108 ligation. When Ly108 is engaged in trans during cell–cell interactions, Ly108–CD3ζ interactions are promoted in a manner that uniquely depends on Ly108 TM domain, leading to more efficient CD3ζ dephosphorylation. Whereas replacement of the Ly108 TM domain still allows the constitutive, colocalization-dependent inhibition of CD3ζ phosphorylation, it abrogates the ligation-dependent Ly108–CD3ζ interactions and CD3ζ dephosphorylation, and it abolishes the suppression on Ag-triggered T–B adhesion. These results offer new insights into how SAP and Ly108 antagonistically modulate the strength of proximal TCR signaling and thereby control cognate T cell–APC interactions.

show abstract

Human Natural Killer Receptors, Co‐Receptors, and Their Ligands

Biassoni

Malnati

2009

CP in Immunology

View full text Add to dashboard Cite

In the last 20 years, the study of human natural killer (NK) cells has moved from the first molecular characterizations of very few receptor molecules to the identification of a plethora of receptors displaying surprisingly divergent functions. Our laboratory has contributed to the description of inhibitory receptors and their signaling pathways, important in fine regulation in many cell types, but unknown until their discovery in the NK cells. Inhibitory function is central to regulating NK-mediated cytolysis, with different molecular structures evolving during speciation to assure its persistence. Only in the last ten years has it become possible to characterize the NK triggering receptors mediating natural cytotoxicity, leading to an appreciation of the existence of a cellular interaction network between effectors of both natural and adaptive immunity. This report reviews the contemporary history of molecular studies of receptors and ligands involved in NK cell function, characterizing the ligands of the triggering receptor and the mechanisms for finely regulating their expression in pathogen-infected or tumor cells.

show abstract

NTB-A Receptor Crystal Structure: Insights into Homophilic Interactions in the Signaling Lymphocytic Activation Molecule Receptor Family

Cited by 66 publications

References 54 publications

Structure of CD84 provides insight into SLAM family function

Structure of CD84 provides insight into SLAM family function

SAP-Regulated T Cell–APC Adhesion and Ligation-Dependent and -Independent Ly108–CD3ζ Interactions

Human Natural Killer Receptors, Co‐Receptors, and Their Ligands

Contact Info

Product

Resources

About