Figures & data
Figure 1. Schematic view of integrin activation. The integrin α/β heterodimer is believed to convert between the bent structure of the resting state and the extended arrangement of the activated state. The crystal structure of the αvβ3 integrin ectodomain (1JV2 from the PDB) with the Gottschalk model of the α/β TM domain complex Citation[16] is shown as the inactive integrin. This figure is reproduced in colour in Molecular Membrane Biology online, where talin is coloured yellow, the αIIb subunit is cyan and the β3 integrin subunit is red. The nomenclature for the different integrin regions is indicated.
![Figure 1. Schematic view of integrin activation. The integrin α/β heterodimer is believed to convert between the bent structure of the resting state and the extended arrangement of the activated state. The crystal structure of the αvβ3 integrin ectodomain (1JV2 from the PDB) with the Gottschalk model of the α/β TM domain complex Citation[16] is shown as the inactive integrin. This figure is reproduced in colour in Molecular Membrane Biology online, where talin is coloured yellow, the αIIb subunit is cyan and the β3 integrin subunit is red. The nomenclature for the different integrin regions is indicated.](/cms/asset/d6f420ee-14c3-4c4e-9582-a1ce6a3f1255/imbc_a_327155_f0001_b.jpg)
Figure 2. Interactions of the transmembrane (TM) and cytoplasmic αIIb and β3 integrin domains. (A) Sequences of the TM and cytoplasmic domains. The residues believed to reside within the bilayer are boxed. The borders were determined by sequence comparison to other α and β subunits whose membrane bordering residues have been determined experimentally Citation[36]. The TM domain residue pairs, identified as being at the heterodimeric interface by cysteine-scanning experiments Citation[11], are indicated by lines, while the salt-bridge between αIIb-R995 and β3-D723, inferred from mutational experiments on intact integrins Citation[25], is indicated by +/− symbols. The binding regions for talin Citation[49], filamin Citation[54], dok1 Citation[56], kindlin3 Citation[59] and ICAP-1α Citation[63] are indicated on the β3-tail. Dok1 binding is much more significant in phosphorylated β3; its binding region is distinguished by a dashed line. ICAP-1α has been shown to bind preferentially to β1 integrins Citation[63]; the dotted line indicates the equivalent binding region in β1 tails. The two β NPxY-type sequences and the αIIb double proline motif are highlighted in bold. (B) Postulated models of changes in the TM domains during integrin activation. The initially interacting TM domains in the inactive state (second from left) shift vertically within the bilayer in the piston model (left). In the scissor model (second from right), the angle between the helices increases following activation. The two TM domains separate completely in the separation model (far right). The αIIb subunit is shown in cyan, and the β3 subunit in red. The inset diagram illustrates ‘snorkelling’ of residue K716, which allows the positively charged amine in the lysine side-chain to interact with the negatively charged lipid head groups. Also shown is the side-chain of W715, which lies at the interface between the lipid head groups and tails Citation[37]. (C) Model of integrin activation by talin (yellow). Binding of talin to the membrane proximal and NPLY regions of the β3 tail shifts the equilibrium to the right, activating the integrin. Binding of other PTB domains, such as dok1 (blue), can occur in the resting state (left). Phosphorylation of the β3 tail can switch the affinity preference from talin to dok1 and may play a role in regulating activation Citation[56]. (D) Overlay of the talin/PIPK1γβ3 complex Citation[49], with the calculated model of the integrin αIIb/β3 TM and membrane proximal complex (co-ordinates kindly provided by K. Gottschalk Citation[16]), over β3 residues 722–727. The talin F3 domain (yellow) overlaps with the αIIb structure. The chimeric PIPK1γ/β3 peptide is shown in magenta. (E) Filamin (green) interacts with the β-tail between the two NPxY-type motifs Citation[54]. Y747 from the β-tail is indicated. Structure figures were prepared using Molmol Citation[64], and incorporate structures 2rmz, 2h7d, 2v76, 2brq from the PDB.
![Figure 2. Interactions of the transmembrane (TM) and cytoplasmic αIIb and β3 integrin domains. (A) Sequences of the TM and cytoplasmic domains. The residues believed to reside within the bilayer are boxed. The borders were determined by sequence comparison to other α and β subunits whose membrane bordering residues have been determined experimentally Citation[36]. The TM domain residue pairs, identified as being at the heterodimeric interface by cysteine-scanning experiments Citation[11], are indicated by lines, while the salt-bridge between αIIb-R995 and β3-D723, inferred from mutational experiments on intact integrins Citation[25], is indicated by +/− symbols. The binding regions for talin Citation[49], filamin Citation[54], dok1 Citation[56], kindlin3 Citation[59] and ICAP-1α Citation[63] are indicated on the β3-tail. Dok1 binding is much more significant in phosphorylated β3; its binding region is distinguished by a dashed line. ICAP-1α has been shown to bind preferentially to β1 integrins Citation[63]; the dotted line indicates the equivalent binding region in β1 tails. The two β NPxY-type sequences and the αIIb double proline motif are highlighted in bold. (B) Postulated models of changes in the TM domains during integrin activation. The initially interacting TM domains in the inactive state (second from left) shift vertically within the bilayer in the piston model (left). In the scissor model (second from right), the angle between the helices increases following activation. The two TM domains separate completely in the separation model (far right). The αIIb subunit is shown in cyan, and the β3 subunit in red. The inset diagram illustrates ‘snorkelling’ of residue K716, which allows the positively charged amine in the lysine side-chain to interact with the negatively charged lipid head groups. Also shown is the side-chain of W715, which lies at the interface between the lipid head groups and tails Citation[37]. (C) Model of integrin activation by talin (yellow). Binding of talin to the membrane proximal and NPLY regions of the β3 tail shifts the equilibrium to the right, activating the integrin. Binding of other PTB domains, such as dok1 (blue), can occur in the resting state (left). Phosphorylation of the β3 tail can switch the affinity preference from talin to dok1 and may play a role in regulating activation Citation[56]. (D) Overlay of the talin/PIPK1γβ3 complex Citation[49], with the calculated model of the integrin αIIb/β3 TM and membrane proximal complex (co-ordinates kindly provided by K. Gottschalk Citation[16]), over β3 residues 722–727. The talin F3 domain (yellow) overlaps with the αIIb structure. The chimeric PIPK1γ/β3 peptide is shown in magenta. (E) Filamin (green) interacts with the β-tail between the two NPxY-type motifs Citation[54]. Y747 from the β-tail is indicated. Structure figures were prepared using Molmol Citation[64], and incorporate structures 2rmz, 2h7d, 2v76, 2brq from the PDB.](/cms/asset/31bd6af7-5821-4131-b959-b96bb8e3a911/imbc_a_327155_f0002_b.jpg)