Structural basis of transmembrane domain interactions in integrin signaling

Cell surface receptors of the integrin family are pivotal to cell adhesion and migration. The activation state of heterodimeric alpha beta integrins is correlated to the association state of the single-pass alpha and beta transmembrane domains. The association of integrin alpha IIb beta 3 transmembrane domains, resulting in an inactive receptor, is characterized by the asymmetric arrangement of a straight (alpha IIb) and tilted (beta 3) helix relative to the membrane in congruence to the dissociated structures. This allows for a continuous association interface centered on helix-helix glycine-packing and an unusual alpha IIb(GFF) structural motif that packs the conserved Phe-Phe residues against the beta 3 transmembrane helix, enabling alpha IIb(D723) beta 3(R995) electrostatic interactions. The transmembrane complex is further stabilized by the inactive ectodomain, thereby coupling its association state to the ectodomain conformation. In combination with recently determined structures of an inactive integrin ectodomain and an activating talin/beta complex that overlap with the alpha beta transmembrane complex, a comprehensive picture of integrin bi-directional transmembrane signaling has emerged.