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J. Biol. Chem., Vol. 280, Issue 43, 36158-36164, October 28, 2005

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Dpp-responsive Silencers Are Bound by a Trimeric Mad-Medea Complex^*

From the Laboratory of Genetics, University of Wisconsin, Madison, Wisconsin 53706

Transcriptional regulation by transforming growth factor- signaling is mediated by the Smad family of transcription factors. It is generally accepted that Smads must interact with other transcription factors to bind to their targets. However, recently it has been shown that a complex of the Drosophila Smad proteins, Mad and Medea, binds with high affinity to silencer elements that repress brinker and bag of marbles in response to Dpp signaling. Here we report that these silencers are bound by a heterotrimer containing two Mad subunits and one Medea subunit. We found that the MH1 domains of all three subunits contributed directly to sequence-specific DNA contact, thus accounting for the exceptionally high stability of the Smad-silencer complex. The Medea MH1 domain binds to a canonical Smad box (GTCT), whereas the Mad MH1 domains bind to a GC-rich sequence resembling Mad binding sites previously identified in Dpp-responsive enhancer elements. The consensus for this sequence, GRCGNC, differs from that of the canonical Smad box, but we found that Mad binding nonetheless required the same -hairpin amino acids that mediate base-specific contact with GTCT. Binding was also affected by alanine substitutions in Mad and Med at a subset of basic residues within and flanking helix 2, indicating a contribution to binding of the GRCGNC and GTCT sites. The slight alteration of the Dpp silencers caused them to activate transcription in response to Dpp signaling, indicating that the potential for Smad complexes to recognize specific targets need not be limited to repression.

Received for publication, June 24, 2005 , and in revised form, August 12, 2005.

^* This work was supported by a grant from the National Science Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Laboratory of Genetics, University of Wisconsin, 445 Henry Mall, Madison, WI 53706. Tel.: 608-262-2456; Fax: 608-262-2976; E-mail: alaughon{at}wisc.edu.

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