Understand the Functions of Scaffold Proteins in Cell Signaling by a Mesoscopic Simulation Method.

Abstract:

:Scaffold proteins are central players in regulating the spatial-temporal organization of many important signaling pathways in cells. 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. However, most scaffold proteins tend to simultaneously bind more than one signaling molecule, which leads to the spatial assembly of multimeric protein complexes. The kinetics of these protein oligomerizations are difficult to quantify by traditional experimental approaches. 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. We applied this new technique to a simple network system that contains three molecules. One molecule in the network is a scaffold protein, whereas the other two are its binding targets in the downstream signaling pathway. 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. 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. 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. In summary, this study showcases the capability of computational simulation in understanding the general principles of scaffold protein functions.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Su Z,Dhusia K,Wu Y

doi

10.1016/j.bpj.2020.10.002

subject

Has Abstract

pub_date

2020-11-17 00:00:00

pages

2116-2126

issue

10

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(20)30769-4

journal_volume

119

pub_type

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