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61 The modular logic of signaling proteins: building allosteric switches from simple binding domains Wendell A Lim Many eukaryotic signal transduction proteins have component- found in human proteins [3]. Thus, the fundamental based architectures: they are built from combinations of modular domain toolkit, despite changing little since the protein interaction domains and catalytic domains. Intact, these evolution of the roundworm, appears to have been used in proteins display the sophisticated allosteric behavior required a combinatorial fashion to increase phenotypic complexity. for cellular regulation; the protein’s output activity is tightly repressed under basal conditions, but can be robustly Although much is known about the structure and mechanism activated by a specific set of input effector ligands. of individual signaling domains, our understanding of how A combination of structural, biophysical and computational these simple modules are used in combination to build studies is beginning to shed light on the fundamental complex switches lags far behind. This review will therefore principles governing this type of modular allostery. focus on the mechanism of ‘modular allosteric switches’: multidomain proteins with a core output activity that, Addresses although efficiently repressed under basal conditions, is Department of Cellular and Molecular Pharmacology, Department of robustly activated by a specific set of input ligands. We Biochemistry and Biophysics, University of California, San Francisco, would like to understand how these domains are assembled CA 94143-0450, USA; e-mail: wlim@itsa.ucsf.edu to yield sophisticated switch behavior, analogous to the way in Current Opinion in Structural Biology 200