Affinity regulation: MIDAS Bonds in CD11's

The metal ion-dependent adhesion site (MIDAS) is believed to be the site on the alpha chain of LFA-1 (alpha-L, CD11a) which binds ligand (ICAM-1, ICAM-2, or ICAM-3). Although it is likely to be a critical portion of the ligand-binding site, other parts of LFA-1 may also make important contributions, notably the MIDAS site on CD18, and the 4th and 5th repeats of CD11a.

The MIDAS motif consists of DxSxS...T...D, and is equally central to ligand binding for both CD11a/CD18 (LFA-1) and CD11b/CD18 (Complement receptor type 3, CR3).

X-ray crystallographic analyses of the I domains of CD11a and CD11b have identified the atoms of the I domain which bind directly to the metal ion. In all cases examined to date, one of the six possible coordination sites of the metal ion is exposed at the surface, and is not occupied by an I domain residue. It is a popular hypothesis that this exposed face of the metal ion binds directly to an acidic residue in the ligand, such as E34 in ICAM-1. Indeed, in one crystal (1IDO.PDB), the metal ion was bound to E314 of the adjacent I domain.

Two crystal forms of CD11b's I domain suggested (Lee/Liddington) a mechanism for the configurational change believed to control the affinities of leukocyte integrins for their ligands. In the active form, five faces of the metal ion are occupied by uncharged serines, threonine, or water. This leaves the metal electropositive and 'hungry' for a negative charge, such as a glutamate on the ligand. In the inactive form, the threonine moves away from the metal, and a negatively charged aspartate moves into contact with the metal. The resulting charge neutralization leaves the metal with lower affinity for a ligand anion. Both the magnesium and manganese crystals of CD11a's I domain (Qu/Leahy) are in the 'inactive' configuration, according to this hypothesis.

* = contacting metal: O ~2.2A, Cl ~2.6A
.. = second layer from metal, >4A
-OH  uncharged -COO- charged
CD11b D140 S142 S144 T209 D242 Water Cl- E314
.. * * * .. 2*   *
.. * * .. * 3*    
CD11a D137 S139 S141 T206 D239 Water Cl-  
1LFA Mn .. * * .. * 2* *        
1ZOO Mg .. * * .. * 2* *        
1ZOP Mn .. * * .. * 2* *        


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