Description
Integrin alphaLbeta2 is one of three beta2 integrin adhesion proteins. The non-covalent heterodimer of 180kD aL/CD11a and 95kD b2/CD18 integrin subunits is expressed on virtually all leukocytes. The ligand binding site of LFA-1 is in the N-terminal head region, formed by an interaction of the vWFA (I, I-like) domains from each subunit, and the aL betapropeller structure. The aL subunit contains domains termed thigh, calf-1 and calf-2, while the b2 subunit contains a PSI region and four cysteine-rich I-EGF folds. Each subunit has a transmembrane sequence and a short cytoplasmic tail connected to the cytoskeleton. Upon activation by "inside-out" signaling, clustering, or Mg2+ or Mn2+ binding to metal ion-dependent adhesion sites within the vWFA domains, the molecule unfolds from its inactive, "closed" conformation to expose ligand binding sites. Active aLb2 binds ICAM-1/CD54, ICAM-2, ICAM-3 and JAM-A. The adhesion stabilizes interactions between T cells and antigen-presenting cells, decreases the T cell activation threshold and facilitates leukocyte transendothelial migration to sites of inflammation. A constitutively active construct severely impairs immune responses, demonstrating that both activation and de-activation are important. Mutations of b2, especially in the vWFA domain, cause leukocyte adhesion deficiency (LAD-1) and susceptibility to bacterial infections. The 1088aa human aL/CD11b is 73-74% aa identical to mouse and rat, and 79-80% aa identical to bovine, porcine, ovine, goat and canine. The 678aa human b2/CD18 shares 81-83% aa sequence identity with mouse, rat, bovine, canine, goat, ovine and porcine b2 ECD. A second human aL isoform has 53 aa inserted after aa 954 in the ECD. The 678 aa human b 2/CD18 ECD shares 81-83% aa sequence identity with mouse, rat, bovine, canine, goat, ovine and porcine b2 ECD