It has been suggested that although scaffold proteins are not direct elements of signal transduction, they are able to offer compartmentalization in a crowded and heterogeneous environment of cytosol, within which the biochemical processes are greatly facilitated by proximity ( 6). These molecules are called scaffold proteins ( Fig. 1 a ( 4, 5)). One class of proteins was found to play an essential role in such regulation by providing physical platform of assembling relevant signaling components ( 3). The high efficiency and fidelity of information transfer during this process is assured by the spatial and temporal regulation of molecules that are involved in the network ( 2). The information flow in an elaborately designed cell signaling network is not a stochastic process ( 1). In summary, this study showcases the capability of computational simulation in understanding the general principles of scaffold protein functions. Moreover, by changing the flexibility of the linker between two binding motifs, our results suggest that the conformational fluctuations in a scaffold protein play a positive role in recruiting downstream signaling molecules. By applying the new simulation method to the model, we show that the scaffold proteins will promote not only thermodynamics but also kinetics of cell signaling given the premise that the interaction between the two signaling molecules is transient. Each of the three molecules in the system contains two binding motifs that can interact with each other and are connected by a flexible linker. One molecule in the network is a scaffold protein, whereas the other two are its binding targets in the downstream signaling pathway. We applied this new technique to a simple network system that contains three molecules. To understand the functions of scaffold proteins in cell signaling, we developed a, to our knowledge, new hybrid simulation algorithm in which both spatial organization and binding kinetics of proteins were implemented. The kinetics of these protein oligomerizations are difficult to quantify by traditional experimental approaches. However, most scaffold proteins tend to simultaneously bind more than one signaling molecule, which leads to the spatial assembly of multimeric protein complexes. They offer physical platforms to downstream signaling proteins so that their transient interactions in a crowded and heterogeneous environment of cytosol can be greatly facilitated. Scaffold proteins are central players in regulating the spatial-temporal organization of many important signaling pathways in cells.

Molecular scaffold protein