Abstract
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 β3 subunit of the platelet αIIbβ3 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 β3 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 Cys567–Cys581 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 αIIbβ3 integrin, which are essential for the native activation process.
Highlights
Integrins are a broad family of membrane-associated heterodimers that mediate any interaction between a cell and its surrounding tissues
The Structural Fluctuation of the Simulated Proteins The WT protein and the in-silico created C583S mutant of the b3 subunit were subjected to Molecular Dynamics (MD) simulations for 35 ns
The lower leg of the b3 subunit is built of a sequence of rigid elements: the four integrin-epidermal growth factor-like (I-EGF) domains and the b-tail are all b-sheet structures that are stabilized by internal disulfide bonds
Summary
Integrins are a broad family of membrane-associated heterodimers that mediate any interaction between a cell and its surrounding tissues. The human platelet integrin aIIbb, termed glycoprotein IIb/IIIa, is a typical representative of this wide family of cell adhesion receptors [1]. AIIbb plays a crucial role in mediating platelet adhesion and aggregation by serving as a fibrinogen and a von Willebrand factor receptor. The binding of ligands to aIIbb is strongly regulated; following activation by inside-out signals, the integrin goes through conformational changes resulting in ligand binding, clustering of the aIIbb receptors, tyrosine phosphorylation and cytoskeleton rearrangements [2,3]. The precise mechanism of aIIbb activation is still unknown, but the crystallographic data suggest equilibrium between a bent and an extended conformation, which is able to bind a ligand. Several intermediate affinity states have been suggested [4,5,6,7], and an alternative model involving release of a ‘‘deadbolt’’ created by an interface of a two distant domains has been proposed [8,9,10]
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