IgSF Molecular Architecture and Interactions in the Context of Function

The Ig-superfold appears to provide a stable structural platform capable of supporting many variations on the theme of specific ligand recognition. The interactions it mediates can be high affinity (nanomolar range, as in cytokine receptor interactions, such as between FGF and FGF receptor), medium affinity (micromolar to nanomolar range, as immunoglobulin-antigen complexes), or weak affinity (millimolar range, as exemplified by many of the cell adhesion molecule interactions), but always a high degree of specificity is retained. For the cell adhesion type of interaction, it has been proposed that a predominance of electrostatic, in particular hydrogen-bond-based, binding provides the mechanism for generating only low affinity while maintaining specificity [35]. In each case, the binding affinities, kinetics, and avidity are matched to the requisite functional role of the interaction.

In addition to the adaptability of the interaction surface it can provide, the modular nature of the Ig-superfold also lends itself well to the formation of large multi-domain or multi-molecular assemblies. Such assemblies provide additional mechanisms by which to modulate function. For example, the 17 Ig-domain extracellular region of sialoadhesin may serve to present the sialic acid binding N-terminal domain at sufficient distance above the cell surface that it avoids any cis-type interactions with glycan ligands on the same cell surface [6]. Conversely, the closely matched sizes of interaction complexes such as CD2-CD58, B7-1-CTLA4, and MHC-TCR may be integral to the formation of supra-molecular assemblies between cells [36,37]—for example, the immunological synapse. Such assemblies increasingly are perceived as the deciding factor in the biological outcome of a cell-cell recognition event.

CTLA-4 homodimer_CTLA-) homed imer

07-1 homodrmer B7-1 homodim^r [37-: "lomr-c tc"

Figure 4 Crystal packing contacts for the structure of B7-1-CTLA-4 complex; an example of a zipper-like array compatible with cell-cell interaction. (PDB code 1I8L [31])

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