Towards a structural model of an integrin

Integrins are currently viewed as the principal family of extracellular matrix receptors. The interactions mediated by integrins are responsible for certain typical properties of adhesive cells, such as attachment and migration, but these molecules are also recognized to contribute to intracellular signalling processes, either by transducing signals themselves or by enabling and/or coordinating signalling via other receptor systems. As yet, the structural basis of integrin function is unknown, although detailed computer-based predictions have suggested working models for integrin tertiary structure. In this chapter, I will review this information and discuss recent studies examining the molecular basis of integrin regulation using stimulatory and inhibitory monoclonal antibodies (mAbs). Through the use of sensitive isolated integrin-binding assays, stimulatory mAbs have been found to function either by inducing shape changes in integrins or by selectively recognizing and stabilizing active and ligand-occupied conformations of integrins, while blocking mAbs were found to be allosteric inhibitors of ligand binding that report specific ligand engagement events. This information has improved our understanding of the composition of the integrin ligand-binding pocket and the structural basis of integrin activation.