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Fig. 1. The three conformations of a β2 (ITGB2) integrin. Integrins are heterodimeric glycoproteins comprising non-covalently linked - and β-subunits. Each subunit consists of a large extracellular region, a single hydrophobic transmembrane domain and a short cytoplasmic tail. The extracellular region of the -subunit comprises an N-terminal seven-bladed β-propeller domain followed by three β-sandwich domains (termed thigh, calf 1 and calf 2). Nine of the 18 -subunits (including the four β2-family integrins) also contain an I domain, which is inserted in the upper face of the β-propeller. The β-subunit has an N-terminal cysteine-rich PSI (plexin-semaphorin-integrin) domain, a β-sandwich hybrid domain, a β I-like domain, four integrin EGF-like repeats (I-EGF1 to I-EGF1-4) and a β-tail domain (βTD). In the tertiary structure, the I domain is inserted in the hybrid domain. When present, the I domain is the exclusive site of ligand binding. (A) Bent–inactive. Integrins are bent between I-EGF1 and I-EGF2 in the β-subunit and at a small Ca²⁺-binding loop, known as the `genu', between the thigh and calf1 domains in the -subunit. Thus, the inactive integrin is in a V shape with the ligand-binding I domain close to the membrane. There is close association between the - and β-subunits in the membrane-proximal region. (B) Extended–intermediate affinity. Inside-out signalling extends the integrin in a `switchblade-like' motion, orientating the I domain away from the membrane for optimal ligand binding. This epitope for the monoclonal antibody (mAb) KIM127, which is located on I-EGF2 and obscured in the bent formation, becomes exposed. The KIM127 epitope thus serves as a marker for the extended β2 integrin. (C) Extended with open conformation–high affinity. Local conformational changes within the and β I domains, potentially generated by shear force, result in the hybrid domain swinging out and the subunit separating at the genu. This remodelling of the I domain ligand-binding site forms the epitope for mAb 24 and causes increased affinity for ligand.

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