Fig. 2. Integrin conformation-function relationships: a model. A five-component model illustrating conformational changes that are associated with inside-out and outside-in integrin signalling. The -subunit is in red and the β-subunit in blue. The figure shows the three major conformational states that have been identified so far: inactive (A), primed (B) and ligand bound (C) (ligand is represented by a green triangle), together with possible intermediate conformers. Panels A-C represent conformations that mediate inside-out signalling, and panels D and E, outside-in signalling (the direction is indicated by red arrows). (A) Inactive integrin adopts a compact, most probably bent conformation in which the - and β-subunit leg, transmembrane and cytoplasmic domains are closely associated. (B) The inherent flexibility of the knees allows for a degree of movement or `breathing' in this structure. Intracellular signals, culminating in the binding of talin (orange oval) to the β-subunit tail, causes relaxation of the leg restraints, allowing some further unbending that is sufficient to expose the epitopes of stimulatory antibodies in the leg regions (represented by yellow stars). A concomitant small outward movement of the hybrid domain primes the ligand-binding pocket to achieve a high-affinity conformation that is ready to accept ligand. The point at which a high-affinity conformation is reached may be integrin- and agonist-specific, and might take place before the receptor is fully extended. (C) The primed integrin binds ligand, which represents the end-point of inside-out signalling. At this stage the integrin is probably in an extended conformation, but the hybrid domain might remain in its primed position and, although some destabilisation and rearrangement of the legs has occurred, their degree of separation is not known. (D,E) The binding of talin and ligand initiate focal contact formation. As the cytoskeleton matures, tension (D, blue arrows) is generated on the integrin receptor across the cell membrane. (E) The force applied to the integrin headpiece triggers further outward movement of the hybrid domain, strengthening receptor-ligand binding and allowing the formation of stable focal adhesions and the initiation of intracellular signalling cascades (green arrow), the end-point of outside-in signalling.