Conformational Changes in Talin on Binding to Anionic Phospholipid Membranes Facilitate Signaling by Integrin Transmembrane Helices
Figure 7
Atomistic simulation of a talin/integrin TM complex with a lipid bilayer (simulation αβ-talh2o-AT; see Table 1).
A. The talin/integrin TM complex, indicating the four distances (d1 to d4) used to monitor the packing of the TM helices during the simulation. B. Interhelical distances (d1 to d4) as a function of time for the αβ-talh2o-AT simulation. Distance d1 shows the separation between the centers of mass of the backbone particles of residues 965–968 of integrin α and residues 694–697 of integrin β as a function of time. Similarly d2, d3 and d4 show the same distances for the α970–973/β700–703, α976-797/β705–708 and α984–987/β714–717 residue groups respectively. Note that all groups are located in the helical region of the integrin TM region. C. Proposed mechanism for the integrin inside-out activation by the bound talin head domain. Electrostatic interactions of talin with negatively charged lipid headgroups promotes reorientation of the talin head domain in a plane perpendicular to the bilayer normal. In turn this rotates the β integrin tail (∼30°) perpendicular to the membrane, disrupting the interactions in both the αIIb/β3 IMC and OMC TM regions. The weakened αIIb/β3 interactions, together with a ∼15° increase in the β TM helix tilt angle relative to the bilayer normal, results in a scissoring movement of the TM regions of the two helices with a modified IMC at the center of the scissors. The scissoring movement is followed by complete dissociation of the two integrin TM helices.