Editors' ChoiceScaffold Proteins

Beyond the Call of Duty

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Science Signaling  24 Mar 2009:
Vol. 2, Issue 63, pp. ec106
DOI: 10.1126/scisignal.263ec106

Scaffold proteins are important organizers of signaling pathways because they act as platforms to bring together individual signaling molecules, thus making their interactions more efficient (see Seeliger and Kuriyan). Ste5 is a scaffold protein that organizes the following components of a mitogen-activated protein kinase (MAPK) pathway that mediates the mating response in yeast: Ste11, a MAPK kinase kinase; Ste7, a MAPK kinase; and Fus3, a MAPK. Building on previous work that showed that Ste5 partially allosterically regulates the activity of Fus3, Good et al. investigated how Ste5 might influence the ability of Ste7 to differentially phosphorylate Fus3 and a similar substrate, the MAPK Kss1. Ste7-mediated activation of Kss1 triggers filamentation in response to starvation. Through a series of binding studies, in vitro kinase assays, and structure determinations of the purified proteins of interest, the authors showed that, whereas Kss1 was efficiently phosphorylated by Ste7, Fus3 was a poor substrate; efficient phosphorylation of Fus3 by Ste7 required the presence of Ste5. An ~200 amino acid residue fragment of Ste5 substantially increased phosphorylation of Fus3 by Ste7, whereas it had no effect on the phosphorylation of Kss1. This region, termed the Ste5 minimal scaffold (Ste5-ms), bound tightly to Ste7, but weakly to Fus3, and is distinct from a previously characterized binding site for Fus3. Thus, the authors suggest that, in addition to its role in tethering components of the MAPK cascade, Ste5 acts as coactivator of the phosphorylation of Fus3, but not of other Ste7 targets, by “unlocking” its conformation.

M. Good, G. Tang, J. Singleton, A. Reményi, W. A. Lim, The Ste5 scaffold directs mating signaling by catalytically unlocking the Fus3 MAP kinase for activation. Cell 136, 1085–1097 (2009). [Online Journal]

M. A. Seeliger, J. Kuriyan, A MAPK scaffold lends a helping hand. Cell 136, 994–996 (2009). [Online Journal]

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