Stochastic machines as a colocalization mechanism for scaffold protein function

• We constructed a model for the Axin–β-catenin–GSK3β–CKIα complex.
• The structured proteins bind to Axin’s longest disordered region.
• The resulting structure has structured domains colocalized via flexible linkers.
• β-Catenin phosphorylation by the kinases is proposed to occur by random movements.
• Unlike typical machines, the stochastic machine parts move without coordination.

The axis inhibition (Axin) scaffold protein colocalizes β-catenin, casein kinase Iα, and glycogen synthetase kinase 3β by their binding to Axin’s long intrinsically disordered region, thereby yielding structured domains with flexible linkers. This complex leads to the phosphorylation of β-catenin, marking it for destruction. Fusing proteins with flexible linkers vastly accelerates chemical interactions between them by their colocalization. Here we propose that the complex works by random movements of a “stochastic machine,” not by coordinated conformational changes. This non-covalent, modular assembly process allows the various molecular machine components to be used in multiple processes.