On the Activation of Integrin aIIbb3: Outside-in and Inside-out Pathways

Integrin aIIbb3 is a member of the integrin family of transmembrane proteins present on the plasma membrane of platelets. Integrin aIIbb3 is widely known to regulate the process of thrombosis via activation at its cytoplasmic side by talin and interaction with the soluble fibrinogen. It is also reported that three groups of interactions restrain integrin family members in the inactive state, including a set of salt bridges on the cytoplasmic side of the transmembrane domain of the integrin aand b-subunits known as the inner membrane clasp, hydrophobic packing of a few transmembrane residues on the extracellular side between the aand b-subunits that is known as the outer membrane clasp, and the key interaction group of the bA domain (located on the b-subunit head domain) with the bTD (proximal to the plasma membrane on the b-subunit). However, molecular details of this key interaction group as well as events that lead to detachment of the bTD and bA domains have remained ambiguous. In this study, we use molecular dynamics models to take a comprehensive outside-in and inside-out approach at exploring how integrin aIIbb3 is activated. First, we show that talin’s interaction with the membrane-proximal and membrane-distal regions of integrin cytoplasmic-transmembrane domains significantly loosens the inner membrane clasp. Talin also interacts with an additional salt bridge (R734-E1006), which facilitates integrin activation through the separation of the integrin’s aand b-subunits. The second part of our study classifies three types of interactions between RGD peptides and the extracellular domains of integrin aIIbb3. Finally, we show that the interaction of the Arg of the RGD sequence may activate integrin via disrupting the key interaction group between K350 on the bA domain and S673/S674 on the bTD.