Paper Citing NAMD - Abstract
Mehrbod, Mehrdad; Trisno, Stephen; Mofrad, Mohammad R. K.
On the Activation of Integrin alpha IIb beta 3: Outside-in and Inside-out Pathways
BIOPHYSICAL JOURNAL, 105:1304-1315, SEP 17 2013
Integrin alpha IIb beta 3 is a member of the integrin family of transnnembrane proteins present on the plasma membrane of platelets. Integrin alpha IIb beta 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 alpha- and beta-subunits known as the inner membrane clasp, hydrophobic packing of a few transmembrane residues on the extracellular side between the alpha- and beta-subunits that is known as the outer membrane clasp, and the key interaction group of the beta A domain (located on the beta-subunit head domain) with the beta TD (proximal to the plasma membrane on the beta-subunit). However, molecular details of this key interaction group as well as events that lead to detachment of the beta TD and beta 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 alpha IIb beta 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 alpha- and beta-subunits. The second part of our study classifies three types of interactions between RGD peptides and the extracellular domains of integrin alpha IIb beta 3. Finally, we show that the interaction of the Arg of the ROD sequence may activate integrin via disrupting the key interaction group between K350 on the beta A domain and S673/S674 on the beta TD.
