Molecular basis for function

Effects of antibodies

ICAM-1 and ICAM-3 bind to overlapping but different epitopes on LFA-1. Most antibodies to LFA-1 (either the a or (3 chains) or ICAM-1 inhibit adhesion function, some distinguishing between different ICAMs. Inhibitory antibodies often bind to CDlla at the I domain or the EF-hand-like repeats. Rare 'functionally neutral' antibodies neither inhibit nor activate adhesion (e.g. TS2/4), and these are thought to bind to nonfunctional epitopes. Some of these bind to the N-terminal region of CDlla (residues 1-57). A few antibodies activate function. Most of these bind to CD 18, but rare examples bind to CDlla. Some activating antibodies have been shown to reduce the concentration of magnesium required for half-maximal function.

Divalent cations

LFA-1-dependent adhesion requires magnesium, in contrast to some other integrins and cadherins which are calcium dependent. Physiological [Mg2 + |, about 3 mM, is sufficient for optimal LFA-1 function with or without calcium. In the absence of magnesium, calcium supports no adhesion, and calcium reduces the efficacy of magnesium. (A synergistic effect of calcium observed under some circumstances could well result from an influx into the cytoplasm, rather than a direct effect on extracellular LFA-1). Manganese supports LFA-1 function with several times the potency of magnesium, and is useful for experimental maneuvers but is not believed to be bound to LFA-1 under normal conditions. The effects of divalent cations on function are complex and probably involve more than one of the five or more putative divalent cation-binding sites in CDlla/CD18.

The I domain and its MIDAS motif

The I domain of CDHa is believed to be the binding site, or a crucial part of the binding site, for ICAMs. A discontinuous magnesium-binding site has been identified in the I domain, termed the MIDAS motif (metal ion-dependent adhesion site). This motif is made up of AspXSerXSer (where X represents any amino acid) plus Thr and Asp in distant parts of the chain, arranged in proximity to the metal ion in the tertiary structure. In CDlla, magnesium is bound to Asp 13 7GlySerMetSer plus Thr206 and Asp239 (Figure 2). CD18 probably also contains a functional MIDAS motif. Mutation of Aspl34 or Serl36 in CD 18 allowed expression with CDlla or CD lib, but produced loss of ligand binding in each case.

In both CDlla and CD lib, one of the six coordination sites of the magnesium ion is not coordinated by the I domain. This site is likely to bind a negatively charged residue on the ICAM ligand, such as Glu34 in ICAM-1 or Glu37 in ICAM-3, shown by mutagenesis to be critical for binding, and hence probably Glu40 in ICAM-2. It is not clear at present whether this proposed metal-to-ligand bond is essential for ligand binding. Alternatively, the metal may stabilize the necessary binding site, rather than being a critical part of the binding site itself.

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