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Summary: The divalent-cation-dependent binding of αβ heterodimeric integrins to their ligands regulates most cellular processes. Integrin–ligand interactions are tightly controlled by inside-out activation signals. Ligand-bound integrins transduce outside-in signals typical of other receptors. Precise information of how ligands bind to integrins is restricted to that of a small vWF A-type domain present in some α-subunits (αA). Both inside-out and outside-in signals elicit tertiary and quaternary changes in integrins, but the precise nature and scope and of these changes are unknown. The recently solved structures of the extracellular segment of integrin αVβ3 in its unliganded and liganded states are generating exciting new insights into the design, wiring, function and regulation of this protein family. The structures reveal a surprising degree of flexibility at defined regions in the structure that is potentially controlled by cations. The quaternary structure of the ligand-binding region bears a striking resemblance to the nucleotide-binding pocket of G-proteins, implying analogous signaling mechanisms. Structural links exist through which ligand-induced tertiary changes may be translated into quaternary changes and vice versa. The structures also raise the tantalizing hypothesis that αA is a regulated endogenous integrin ligand, so that no special regulatory features are needed in this integrin. These findings provide the framework for new investigations of structure–activity relationships in integrins, with important implications for targeting these receptors therapeutically.

Understanding the molecular basis of a rare inherited disease, Leu-CAM deficiency in humans, has underscored the importance of the cellular component of inflammation and unravelled the complex series of homotypic and heterotypic cell interactions necessary for mobilization of leukocytes to infected sites. Furthermore, this disease has shown that several apparently distinct cellular inflammatory responses (e.g. aggregation, adhesion to endothelium, directed migration and phagocytosis) are mechanistically related and mediated by a set of molecules which belong to a larger group of adhesion molecules (Integrins) mediating similar phenomena critical for immune surveillance, lymphocyte homing, morphogenesis and thrombogenesis. This disease also showed the relative biologic importance of CD11/CD18 in leukocytes. CD11/CD18 are more critical for the functions of phagocytic cells as compared to lymphocytes although similar inhibitory effects of anti-CD11/CD18 mAbs can be demonstrated in vitro. Expression and function of CD11/CD18 is regulated at several levels which include formation of stable heterodimers, qualitative changes in the receptor and quantitative changes in the levels of expression of the receptors and their ligands. We have identified inherited single amino acid substitutions on CD18 which impair heterodimer formation and cell surface expression, thus accounting for the pathogenesis of Leu-CAM deficiency. We also found a stimulus-induced phosphorylation of CD18, which is transient in nature when elicited through other surface receptors. This may be important in regulation of CD11/CD18 receptor avidity, recycling, endocytosis and cross-talk with other receptors. Finally, realization of the profound impairment in the acute cellular inflammatory response present in Leu-CAM deficiency has permitted novel ways of controlling the inflammatory response in several situations were inflammation serves an injurious rather than a beneficial role to the host.

The divalent-cation-dependent binding of alphabeta heterodimeric integrins to their ligands regulates most cellular processes. Integrin-ligand interactions are tightly controlled by inside-out activation signals. Ligand-bound integrins in turn transduce outside-in signals typical of other receptors. Precise information of how ligands bind to integrins is restricted to that of a small vWF A-type domain present in some alpha-subunits (alphaA). Both inside-out and outside-in signals elicit tertiary and quaternary changes in integrins, but the precise nature and scope and of these changes are unknown. The recently solved structures of the extracellular segment of integrin alphaVbeta3 in its unliganded and liganded states are generating exciting new insights into the design, wiring, function and regulation of this protein family. The structures reveal a surprising degree of flexibility at defined regions in the structure that is potentially controlled by cations. The quaternary structure of the ligand-binding region bears a striking resemblance to the nucleotide-binding pocket of G-proteins, implying analogous activation and signaling mechanisms. Structural links exist through which ligand-induced tertiary changes may be translated into quaternary changes and vice versa. The structures also raise the tantalizing hypothesis that alphaA is a regulated endogenous integrin ligand, so that no special regulatory features are needed in this integrin. These findings provide the framework for new investigations of structure-activity relationships in integrins, with important implications for targeting these receptors therapeutically [corrected].