Cell Biology Select

This issue's Cell Biology Select highlights recent studies that improve our understanding of how switches and tuners regulate cellular processes. Two studies encompassing very different processes—programmed cell death and plant lateral root formation—both reveal regulatory switches that work independently of enzyme action. Three other studies present new insights into how cell motility, signal transduction, and periodic gene expression may be tuned. Programmed cell death or apoptosis can be initiated by the formation and clustering of death-inducing signaling complexes (DISCs) induced by Fas ligand. Certain DISCs are formed by Fas receptor (Fas), FADD (Fas-associated death domain), and caspase 8, and the interactions between the death domain of Fas and FADD are pivotal triggers of DISC formation and apoptosis. Scott et al. (2009) now present the 2.7 A ˚ crystal structure of the human Fas-FADD death domain complex. From this structure, the authors surmise that conformational changes in Fas and weak binding interactions between Fas and FADD are the central elements of the molecular switch that triggers DISC formation. The authors observe that the Fas-FADD death domain complex in solution exists in a tetrameric arrangement consisting of four FADD death domains and four Fas death domains. FADD-bound Fas death domains undergo structural rearrangements to adopt an ''open'' conformation. This open Fas conformation creates new interaction surfaces crucial for FADD binding and Fas-Fas interactions within the tetra-meric complex. Importantly, Fas forms weak binding interactions with FADD in the death domain complex. These weak interactions may prevent spurious activation of DISC formation in the absence of Fas ligand. The authors propose that Fas normally oscillates between unstable open and closed conformations. However, upon clustering of Fas induced by Fas ligand during apoptosis initiation, Fas-Fas interactions would promote stabilization of the open conformation, establishing permissive binding sites for FADD. Indeed, Scott et al. find that the expression in cultured cells of a mutant form of Fas prone to adopting the open conformation results in a higher rate of cell death even in the absence of Fas ligand. The investigators also point out that interactions among multiple Fas-FADD complexes would stabilize weak Fas-FADD binding and further promote clustered DISC formation. This model of DISC formation presents a switch mechanism for signaling receptor activation that is dependent only upon conformational changes and does not require enzymatic activity. In plants, the growth hormone auxin directs the formation of lateral roots along the primary root. Laskowski et al. (2009) …