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A Polymerization Switch for Yan

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Science's STKE  27 Jul 2004:
Vol. 2004, Issue 243, pp. tw270
DOI: 10.1126/stke.2432004tw270

In Drosophila, alleviation of transcriptional repression by Yan involves phosphorylation of Yan by the mitogen-activated protein kinase Rolled in response to receptor tyrosine kinase activation. Yan and another protein known as Mae both contain SAM domains, and Mae binds both Yan and Rolled to somehow facilitate the phosphorylation event. Qiao et al. used various methods to show that the SAM domain of Yan forms a polymer structurally similar to that formed by the human ortholog TEL, which has been crystallized. The structure of the Yan SAM polymer was modeled based on the TEL monomer crystal. Point mutations that disrupted self-association of the Yan SAM domain also blocked the ability of Yan (when mutated in the context of the full-length protein) to inhibit transcription of a reporter gene. These polymerization-defective Yan mutants did, however, bind DNA, which suggests that polymerization is required for the repressive activity. In vitro, the SAM domain of Mae bound the SAM domain of Yan and inhibited Yan polymer formation. Mae mutants defective in Yan interaction did not alleviate Yan repression of a reporter gene expression. Crystallization of a fusion protein between the Yan and Mae SAM domains showed that the ML surface of Yan-SAM interacts with the EH surface of Mae SAM in a manner similar to the proposed homomeric interactions of Yan SAM. The authors propose that polymerized Yan has the transcriptional repression activity, and Mae disrupts the formation of the polymer, which allows Rolled to phosphorylate Yan, thus promoting its export from the nucleus. This shifts the equilibrium such that the Yan depolymerizes, alleviating transcriptional repression.

F. Qiao, H. Song, C. A. Kim, M. R. Sawaya, J. B. Hunter, M. Gingery, I. Rebay, A. J. Courey, J. U. Bowie, Derepression by depolymerization: Structural insights into the regulation of Yan by Mae. Cell 118, 163-173 (2004). [Online Journal]

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