Scaffold Proteins: Hubs for Controlling the Flow of Cellular Information

Matthew C. Good et al.
From Science

Mammalian cells contain an estimated 1 billion individual protein molecules, with as many as 10% of these involved in signal transduction. Given this enormous number of molecules, it seems remarkable that cells can accurately process the vast array of signaling information they constantly receive. How can signaling proteins find their correct partners - and avoid their incorrect partners - among so many other proteins?

A principle that has emerged over the past two decades is that cells achieve specificity in their molecular signaling networks by organizing discrete subsets of proteins in space and time. For example, functionally interacting signaling components can be sequestered into specific subcellular compartments (e.g., organelles) or at the plasma membrane. Another solution is to assemble functionally interacting proteins into specific complexes. More than 15 years ago, the first scaffold proteins were discovered—proteins that coordinate the physical assembly of components of a signaling pathway or network. These proteins have captured the attention of the signaling field because they appear to provide a simple and elegant solution for determining the specificity of information flow in intracellular networks.

Scaffold Proteins: Versatile Tools to Assemble Diverse Pathways

Scaffolds are extremely diverse proteins,many of which are likely to have evolved independently. Nonetheless they are conceptually related, in that they are usually composed of multiple modular interaction domains or motifs. Their exact domain composition and order, however, can vary widely depending on the pathways that they organize. In some cases, homologous individual interaction motifs can be found in scaffolds associated with particular signaling proteins. For example, the AKAPs (A- kinase anchoring proteins),which link protein kinase A (PKA) to diverse signaling processes, all share a common short peptide motif that binds to the regulatory subunit of PKA. However, the other domains in individual AKAPs are highly variable, depending on what inputs and outputs the scaffold protein coordinates with PKA. Thus, scaffold proteins are flexible platforms assembled through mixing and matching of interaction domains.

Scaffold proteins function in a diverse array of biological processes. Simple mechanisms (such as tethering) are layered with more sophisticated mechanisms (such as allosteric control) so that scaffolds can precisely control the specificity and dynamics of information transfer. Scaffold proteins can also control the wiring of more complex network configurations—they can integrate feedback loops and regulatory controls to generate precisely controlled signaling behaviors. The versatility of scaffold proteins comes from their modularity, which allows recombination of protein interaction domains to generate new signaling pathways. Cells use scaffolds to diversify signaling behaviors and to evolve new responses. Pathogens can create scaffold proteins that are to their advantage: Their virulence depends on rewiring host signaling pathways to turn off or avoid host defenses. In the lab, scaffolds are being used to build new, predictable signaling or metabolic networks to program useful cellular behaviors.