How Talin Head Domain and Soluble Ligand Contribute to Integrin αIIbβ3 Activation

Abstract

Integrin αIIbβ3 is widely known to regulate the process of thrombosis via activation at its cytoplasmic side by talin and interacting with soluble fibrinogen. Three groups of interactions regulate integrin activation: a set of salt bridges in the cytoplasmic side of the transmembrane domain of integrin α- and β-subunits named as the inner membrane clasp, a hydrophobic packing of a few transmembrane residues on extracellular side between α- and β-subunits that is termed as the outer membrane clasp, and the key interaction group of βA domain and βTD domain. Molecular details of this key interaction group as well as events that lead to detachment of βTD and βA domains have remained ambiguous.Full-length structure of integrin αIIbβ3 embedded in a patch of lipid bilayer was used to simulate its interactions with three soluble RGD ligands as well as talin, using a molecular dynamics software. We showed that talin's interaction with the membrane-proximal and membrane-distal regions of integrin cytoplasmic-transmembrane domains significantly loosens the inner membrane clasp as well as an additional salt-bridge (R734-E1006), which facilitates integrin activation through the separation of integrin's α- and β-subunits. Also, it is shown that interaction of the Arg of the RGD sequence may activate integrin via disrupting the key interaction group between Lys346 on βA domain and Ser663/Ser664 on the βTD. Interestingly, we observed the full dissociation of βA and βTd domains when this interaction group was disrupted and was eventually dissociated as a result of a competition between the Arg of the RGD peptide with Ser664. Consequently, we proposed a mechanistic scenario as a potential mechanism for outside-in activation of integrin αIIbβ3 by soluble RGD ligand that reconciles the switchblade and dead-bolt models for integrin activation.