Signalling scaffolds and local organization of cellular behaviour

Abstract

Scaffold proteins are non-catalytic organizational elements that focus enzyme activity by holding members of a signal transduction cascade in place. They confer bidirectional control on cellular processes through the simultaneous recruitment of signal transduction and signal termination enzymes. Rather than functioning enzymatically, scaffolds formed by pseudokinases and pseudophosphatases can function as allosteric modulators of other signalling enzymes. A-kinase anchor proteins (AKAPs) constrain second-messenger-responsive enzymes, such as protein kinase A, in customized macromolecular units. AKAPs are dynamic participants in local signalling, in part owing to their flexibility in structure, transient interactions and combinatorial assembly of binding partners. Protein scaffolds can also be organized around signal termination enzymes that attenuate signalling or promote the degradation of key enzymes. Three examples of this are the scaffolds that target phosphatases, those that control protein ubiquitylation and those that control acetylation and deacetylation. Covalent modification of a scaffold protein can determine which binding partners are included in the complex and thus provide alternative functionality. As a result, several scaffold proteins have been identified as ultra-sensitive switches that toggle between opposing cellular processes.