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Item INTRINSIC DISORDER, SCAFFOLDS, AND STOCHASTIC MACHINES(Office of the Vice Chancellor for Research, 2010-04-09) Dunker, A. Keith; Xue, Bin; William, Albert; Uversky, Vladimir N.Scaffold proteins bind additional proteins that then carry out multi-step pathways. How do such machines work? Here a new hypothesis is proposed for the complex consisting of axin, two kinases – GSK3β and CK1α, and β-catenin. The pathway involves four discrete phosphorylations of β-catenin by the two kinases. Like many other scaffold proteins, axin is mostly unstructured [1, 2]. With a length of about 800 residues, axin forms two small domains of less than 100 residues each, and uses only a small number of residues, about 20 per interaction, to bind to GSK3β and β-catenin [1], and presumably also to bind to CK1α. Thus, even with the two domains and 3 partners, axin remains mostly unfolded. The hypothesis is that the unstructured axin molecule holds the three globular proteins in very high local concentrations, like three globules on a rope, and that, by random motions, first CK1α and then GSK3β phosphorylate the disordered tail of β-catenin successively four times. The “conformational changes” of axin that lead to acceleration of phosphorylation are neither specific nor coordinated, but rather are entirely stochastic, with stereochemical fit between the enzymes and their targets leading to the correct ordering of the four phosphorylation steps. In this hypothesis, the scaffold protein acts simply as a flexible tether that leads to acceleration of the multiple steps in the pathway by raising the local concentrations of the key components and by allowing the various components the freedom to collide in various orientations until productive collisions result. Thus, the steps of the pathway are carried out by a stochastic machine. This may be a general mechanism for scaffold-based molecular machines.Item Stochastic machines as a colocalization mechanism for scaffold protein function(Wiley, 2013) Xue, Bin; Romero, Pedro R.; Noutsou, Maria; Maurice, Madelon M.; Rüdiger, Stefan G. D.; William, Albert M., Jr.; Mizianty, Marcin J.; Kurgan, Lukasz; Uversky, Vladimir N.; Dunker, A. Keith; Biochemistry and Molecular Biology, School of MedicineThe 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.