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J. Biol. Chem., Vol. 281, Issue 35, 25781-25790, September 1, 2006

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Decapentaplegic-responsive Silencers Contain Overlapping Mad-binding Sites^*

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

Smad proteins regulate transcription in response to transforming growth factor- signaling pathways by binding to two distinct types of DNA sites. The sequence GTCT is recognized by all receptor-activated Smads and by Smad4. The subset of Smads that responds to bone morphogenetic protein signaling recognizes a distinct class of GC-rich sites in addition to GTCT. Recent work has shown that Drosophila Mad protein, the homologue of bone morphogenetic protein rSmads, binds to GRCGNC sites through the same MH1 domain -hairpin interface used to contact GTCT sites. However, binding to GRCGNC requires base-specific contact by two Mad proteins, and here we provide evidence that this is achieved by contact of the two Mad subunits that overlap across the two central base pairs of the site. This topology is supported by results indicating that His-93, which is located at the tip of the Mad -hairpin, is in close proximity to base pairs 2 and 5. Also consistent with the model is disruption of binding by mutation of Glu-39 and Glu-40, which are predicted to lie at the interface of the two overlapping Mad MH1 domains. As predicted from the overlapping model, binding is disrupted by insertion of 1 bp in the middle of the site, whereas insertion of 2 bp creates abutting sites that can be bound by the Mad-Medea heterotrimer without requiring Glu-39 and Glu-40. Overlapping Mad sites predominate in decapentaplegic response elements, consistent with a high degree of specificity in response to signaling.

Received for publication, April 10, 2006 , and in revised form, June 21, 2006.

^* This work was supported by the University of Wisconsin Graduate School. 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, 425G Henry Mall, Madison, WI 53706. Tel.: 608-262-2456; Fax: 608-262-2976; E-mail: alaughon{at}wisc.edu.

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