Structure of CD84 provides insight into SLAM family function

Area of Science:

• Immunology
• Structural Biology
• Molecular Interactions

Background:

• The Signaling Lymphocyte Activation Molecule (SLAM) family comprises receptors modulating adaptive and innate immunity.
• SLAM receptors share a common ectodomain structure with variable domains responsible for ligand recognition.
• CD84, a homophilic SLAM member, enhances IFN-gamma secretion in T cells.

Purpose of the Study:

• To investigate the self-association properties and structural basis of CD84 homophilic interactions.
• To compare CD84 dimerization with other SLAM family members.
• To understand the implications of SLAM family receptor structure and affinity on immune cell function.

Main Methods:

• Biochemical studies to determine CD84 self-association affinity (K(d)).
• X-ray crystallography to determine the 2.0 Å crystal structure of the human CD84 immunoglobulin variable domain.
• Comparative structural analysis with other SLAM family members, such as NTB-A.

Main Results:

• CD84 exhibits strong self-association with a K(d) in the submicromolar range.
• The crystal structure reveals an orthogonal homophilic dimer of CD84, similar to NTB-A.
• Structural and chemical differences at homophilic interfaces prevent undesired heterodimer formation among SLAM family receptors.
• All two-domain SLAM family homophilic dimers share a kinked organization, approximately 140 Å end-to-end.

Conclusions:

• SLAM family homophilic affinities vary significantly, potentially influencing distinct signaling behaviors.
• Conserved structural features of SLAM homophilic dimers facilitate colocalization within the immunological synapse.
• This colocalization mechanism may enable bridging of T cells and antigen-presenting cells.