On the activation of integrin ?IIb?3: outside-in and inside-out pathways.

ABSTRACT: Integrin ?IIb?3 is a member of the integrin family of transmembrane proteins present on the plasma membrane of platelets. Integrin ?IIb?3 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 ?- and ?-subunits known as the inner membrane clasp, hydrophobic packing of a few transmembrane residues on the extracellular side between the ?- and ?-subunits that is known as the outer membrane clasp, and the key interaction group of the ?A domain (located on the ?-subunit head domain) with the ?TD (proximal to the plasma membrane on the ?-subunit). However, molecular details of this key interaction group as well as events that lead to detachment of the ?TD and ?A 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 ?IIb?3 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 ?- and ?-subunits. The second part of our study classifies three types of interactions between RGD peptides and the extracellular domains of integrin ?IIb?3. 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 ?A domain and S673/S674 on the ?TD.

SUBMITTER: Mehrbod M 

PROVIDER: S-EPMC3785890 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature