The structure of the integrin αIIbβ3 transmembrane complex explains integrin transmembrane signalling

Abstract

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 24-and 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.

Structure of an integrin αIIbβ3 transmembrane-cytoplasmic heterocomplex provides insight into integrin activation

“…1D), which may stabilize the relative orientations of the TM helices. The extent of the insertion of these residues may vary depending upon the functional/activation states of the receptor (6,(23)(24)(25). Consistent with previous structural characterization of the cytoplasmic ␣IIb/␤3 complex (7), the TMCD complex also reveals an ␣IIb R 995 /␤3 D 723 salt bridge (Fig.…”

“…Dissociation of the TMs or CTs triggers receptor activation and signaling (7,(10)(11)(12)(13)(14). However, many different computational models for the TM association exist (3-5, 11, 13, 15-18) and the structural analyses of the CT interaction are inconsistent (6)(7)(8)(9)19). Earlier studies failed to observe heterodimeric TMCD interaction in micelles (20), which reflects the technical difficulty in structurally characterizing this kind of transmembrane heterodimers (21).…”

“…1 and 2). Biochemical and structural evidence suggests that the ␣/␤ TMCDs associate via both their TMs (3)(4)(5)(6) and their CTs (7)(8)(9) to maintain integrins in a resting state. Dissociation of the TMs or CTs triggers receptor activation and signaling (7,(10)(11)(12)(13)(14).…”

“…Here, we have successfully determined the NMR structure of the ␣IIb␤3 TMCD heterodimer encompassing complete ␣IIb␤3 TMCD sequences. During the preparation of our manuscript, Lau et al (6) reported the structure of the ␣IIb␤3 TM heterodimer containing TMs and truncated portion of the CTs. Our structure agrees with Lau et al (6) on the TM assembly but differs significantly on the CT portion-the center for communicating signals across the membrane (1,2).…”

Mammary-derived growth inhibitor (MDGI) interacts with integrin α-subunits and suppresses integrin activity and invasion

“…Model of integrin's transmembrane-cytoplasmic part with bound talin was built by combining the experimentally solved structures of integrin aIIbb3 transmembrane-cytoplasmic tail (pdb-code: 2k9j (Lau et al, 2009)) and talin F2-F3-integrinb1D cytoplasmic tail (pdb-code: 3g9w (Anthis et al, 2009)). The continuous model of transmembrane-cytoplasmic part of the integrin b-subunit from above mentioned two structures with integrin a-subunits was based on the sequence alignment of integrin b3 and b1 combined with the RMSD-superpositioning option in BODIL (Lehtonen et al, 2004).…”