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MINIREVIEW

Structures of Integrin Domains and Concerted Conformational Changes in the Bidirectional Signaling Mechanism of _IIbß₃

Instituto de Biomedicina de Valencia, C.S.I.C., 46010 Valencia, Spain

To whom requests for reprints should be addressed at ¹ Instituto de Biomedicina de Valencia, C.S.I.C., Jaime Roig 11, 46010, Valencia, Spain. Email: jcalvete{at}ibv.csic.es

Integrins are heterodimeric type I transmembrane cell-adhesive receptors whose affinity for ligands is regulated by tertiary and quaternary conformational changes that are transmitted from the cytoplasmic tails to the extracellular ectodomains during the transition from the inactive to the active state. Receptor occupancy initiates further structural alterations that transduce signals across the plasma membrane and result in receptor clustering and recruitment of signaling molecules and cytoskeletal rearrangements at the integrin’s cytoplasmic domains. The large distance between the intracellular cytoplasmic domains and the ligand-binding site, which in an extended conformation spans more that 200 Å, imposes a complex mechanism of interdomain communication for the bidirectional information flow across the plasma membrane. Significant progress has recently been made in elucidating the crystal and electron microscopy structures of integrin ectodomains in its unliganded and liganded states, and the nuclear magnetic resonance solution structures of stalk domains and the cytoplasmic tails. These structures revealed the location of sites that are functionally important and provided the basis for defining new models of integrin activation and signaling through bidirectional conformational changes, and for understanding the structural basis of the cation-dependent ligand-binding specificity of integrins. Platelet integrin _IIbß₃ has served as a paradigm for many aspects of the structure and function of integrins The aim of this minireview is to combine recent structural and biochemical studies on integrin receptors that converge into a model of the tertiary and quaternary conformational changes in _IIbß₃ and other homologous integrins that propagate inside-out and outside-in signals.

Key Words: integrins • conformational changes • bidirectional signaling • _IIbß₃

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