The structure of the integrin aIIbb3 transmembrane complex explains integrin transmembrane signalling

Heterodimeric integrin adhesion receptors regulate cell migration, survival and differentiation in metazoa by communicating signals bi-directionally across the plasma membrane. Protein engineering and mutagenesis studies have suggested that the dissociation of a complex formed by the single-pass transmembrane (TM) segments of the a and b subunits is central to these signalling events. Here, we report the structure of the integrin aIIbb3 TM complex, structure-based site-directed mutagenesis and lipid embedding estimates to reveal the structural event that underlies the transition from associated to dissociated states, that is, TM signalling. The complex is stabilized by glycine-packing mediated TM helix crossing within the extracellular membrane leaflet, and by unique hydrophobic and electrostatic bridges in the intracellular leaflet that mediate an unusual, asymmetric association of the 24and 29-residue aIIb and b3 TM helices. The structurally unique, highly conserved integrin aIIbb3 TM complex rationalizes bi-directional signalling and represents the first structure of a heterodimeric TM receptor complex. The EMBO Journal (2009) 28, 1351–1361. doi:10.1038/ emboj.2009.63; Published online 12 March 2009 Subject Categories: cell & tissue architecture; structural biology