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Molecular and Cellular Biology, June 2006, p. 4134-4148, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01902-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

MAL and Ternary Complex Factor Use Different Mechanisms To Contact a Common Surface on the Serum Response Factor DNA-Binding Domain

Alexia-Ileana Zaromytidou, Francesc Miralles, and Richard Treisman*

Transcription Laboratory, Lincoln's Inn Fields Laboratories, Cancer Research UK London Research Institute, Room 401, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom

Received 29 September 2005/ Returned for modification 17 November 2005/ Accepted 17 March 2006

The transcription factor serum response factor (SRF) interacts with its cofactor, MAL/MKL1, a member of the myocardin-related transcription factor (MRTF) family, through its DNA-binding domain. We define a seven-residue sequence within the conserved MAL B1 region essential and sufficient for complex formation. The neighboring Q-box sequence facilitates this interaction. The B1 and Q-box regions also have antagonistic effects on MAL nuclear import, but the residues involved are largely distinct. Both MAL and the ternary complex factor (TCF) family of SRF cofactors interact with a hydrophobic groove and pocket on the SRF DNA-binding domain. Unlike the TCFs, however, interaction of MAL with SRF is impaired by SRF {alpha}I-helix mutations that reduce DNA bending in the SRF-DNA complex. A clustered SRF {alpha}I-helix mutation strongly impairs MAL-SRF complex formation but does not affect DNA distortion in the MAL-SRF complex. MAL-SRF complex formation is facilitated by DNA binding. DNase I footprinting indicates that in the SRF-MAL complex MAL directly contacts DNA. These contacts, which flank the DNA sequences protected from DNase I by SRF, are required for effective MAL-SRF complex formation in gel mobility shift assays. We propose a model of MAL-SRF complex formation in which MAL interacts with SRF by the addition of a ß-strand to the SRF DNA-binding domain ß-sheet region, while SRF-induced DNA bending facilitates MAL-DNA contact.

* Corresponding author. Mailing address: Transcription Laboratory, Lincoln's Inn Fields Laboratories, Cancer Research UK London Research Institute, Room 401, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. Phone: (44-20)-7269-3271. Fax: (44-20)-7269-3093. E-mail: Richard.Treisman{at}cancer.org.uk.

Molecular and Cellular Biology, June 2006, p. 4134-4148, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01902-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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