The role of scaffold proteins in information transfer in cellular signaling

VERONICA PARASCO; JACQUES-A. SEPULCHRE; ALEJANDRO COLMAN-LERNER; ALEJANDRA C VENTURA

Buenos Aires

Workshop; XV Giambiagi Winter School, "Information processing in biological sytems, from cells to equations and back".; 2013

Departamento de Física, FCEyN, UBA

Cells propagate information through protein signaling pathways that are part of complexsignal transduction networks. The simplest view of cellular signaling entails a cascade ofmolecular events initiated by the recognition of a stimulus and culminating in the chemicalalteration of an effector molecule. Deregulation of information transmission systems like this one is at the basis of many diseases such as cancer and autoimmunity.Mammalian cells contains an estimated 1 trillion of protein molecules with approximately10% of which are involved in signal transduction. Given the enormous number ofmolecules, it is surprising that cells can accurately process the large amount ofinformation they receive constantly. Even so, different signals are often transmitted bycommon components yet elicit distinct (and appropriate) outcomes. How specificity fromsignal to cellular response is maintained between different signal transduction pathwaysthat share similar (or identical) components? In the recent decades the notion that cellsorganize subgroups of proteins in space and time has appeared. In this direction and about15 years ago, the first scaffold proteins were discovered.Different isolated components from the signaling network have been extensivelystudied and characterized in order to then predict the behavior of the integrated systemfrom the behavior of its parts. This notion is based on the hypothesis that the properties ofthe individual components are not altered as these are interconnected, which is known as"modular organization". However, our work and that of others has shown theoretically andexperimentally (both in vitro and in vivo) that bio-molecular systems cannot always beconnected modularly: the dynamics of the interconnection, which is inherent to thephysics of the system, can dramatically change the behavior of connected modules, an effectthat has been called retroactivity.Bringing together the concepts previously outlined, modular organization and retroactivityon one side and scaffold proteins on the other, the following questions arise: does thebehavior of a signaling module change if it is integrated into a scaffold protein?, what is therelationship between scaffold proteins and retroactivity? Do scaffold proteins have theability to filter out these retroactive effects? Could they function as perfect insulators? Howdoes the structural complexity of scaffold proteins affect its properties?We have characterized the interaction between scaffold proteins and retroactivitythrough a combination of analytical and computational tools using cascades ofcovalent modification cycles.