The structure of the integrin alphaIIbbeta3 transmembrane complex explains integrin transmembrane signalling

• Published in: The EMBO journal Vol. 28; no. 9; p. 1351
• Main Authors: Lau, Tong-Lay, Kim, Chungho, Ginsberg, Mark H, Ulmer, Tobias S
• Format: Journal Article
• Language: English
• Published: England 06.05.2009
• Subjects: Amino Acid Sequence; Cell Membrane - metabolism; Flow Cytometry; Humans; Magnetic Resonance Spectroscopy; Membrane Lipids - chemistry; Membrane Lipids - metabolism; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Platelet Glycoprotein GPIIb-IIIa Complex - chemistry; Platelet Glycoprotein GPIIb-IIIa Complex - genetics; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Signal Transduction - physiology
• ISSN: 1460-2075
• DOI: 10.1038/emboj.2009.63

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 alpha and beta subunits is central to these signalling events. Here, we report the structure of the integrin alphaIIbbeta3 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 alphaIIb and beta3 TM helices. The structurally unique, highly conserved integrin alphaIIbbeta3 TM complex rationalizes bi-directional signalling and represents the first structure of a heterodimeric TM receptor complex.