A Single Disulfide Bond Disruption in the beta 3 Integrin Subunit Promotes Thiol/Disulfide Exchange, a Molecular Dynamics Study

作者：Levin Lihie; Zelzion Ehud; Nachliel Esther; Gutman Menachem; Tsfadia Yossi^*; Einav Yulia

来源：PLos One, 2013, 8(3): e59175.

DOI：10.1371/journal.pone.0059175

The integrins are a family of membrane receptors that attach a cell to its surrounding and play a crucial function in cell signaling. The combination of internal and external stimuli alters a folded non-active state of these proteins to an extended active configuration. The beta 3 subunit of the platelet alpha IIb beta 3 integrin is made of well-structured domains rich in disulfide bonds. During the activation process some of the disulfides are re-shuffled by a mechanism requiring partial reduction of some of these bonds; any disruption in this mechanism can lead to inherent blood clotting diseases. In the present study we employed Molecular Dynamics simulations for tracing the sequence of structural fluctuations initiated by a single cysteine mutation in the beta 3 subunit of the receptor. These simulations showed that in-silico protein mutants exhibit major conformational deformations leading to possible disulfide exchange reactions. We suggest that any mutation that prevents Cys560 from reacting with one of the Cys(567)-Cys(581) bonded pair, thus disrupting its ability to participate in a disulfide exchange reaction, will damage the activation mechanism of the integrin. This suggestion is in full agreement with previously published experiments. Furthermore, we suggest that rearrangement of disulfide bonds could be a part of a natural cascade of thiol/ disulfide exchange reactions in the alpha IIb beta 3 integrin, which are essential for the native activation process.

• 出版日期2013-3-18