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J. Biol. Chem., Vol. 281, Issue 26, 18208-18215, June 30, 2006

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The Carboxyl-terminal Nucleoplasmic Region of MAN1 Exhibits a DNA Binding Winged Helix Domain^*

Sandrine Caputo¹, Joël Couprie¹, Isabelle Duband-Goulet¹, Emilie Kondé, Feng Lin^¶2, Sandrine Braud, Muriel Gondry, Bernard Gilquin¹, Howard J. Worman^¶3, and Sophie Zinn-Justin¹⁴

From the Département d'Ingénierie et d'Etudes des Protéines/Direction des Sciences du Vivant, Bâtiment 152, Commissariat à l'Energie Atomique Saclay, 91191 Gif-sur-Yvette Cedex, France, Institut Jacques Monod-CNRS Unité Mixte de Recherche 7592, Universités Paris 6/7, 2 Place Jussieu, 75251 Paris Cedex 05, France, and ^¶Departments of Medicine and of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York 10032

MAN1 is an integral protein of the inner nuclear membrane that interacts with nuclear lamins and emerin, thus playing a role in nuclear organization. It also binds to chromatin-associated proteins and transcriptional regulators, including the R-Smads, Smad1, Smad2, and Smad3. Mutations in the human gene encoding MAN1 cause sclerosing bone dysplasias, which sometimes have associated skin abnormalities. At the molecular level, these mutations lead to loss of the MAN1-R-Smads interaction, thus perturbing transforming growth factor superfamily signaling pathway. As a first step to understanding the physical basis of MAN1 interaction with R-Smads, we here report the structural characterization of the carboxyl-terminal nucleoplasmic region of MAN1, which is responsible for Smad binding. This region exhibits an amino-terminal globular domain adopting a winged helix fold, as found in several Smad-associated sequence-specific DNA binding factors. Consistently, it binds to DNA through the positively charged recognition helix H3 of its winged helix motif. However, it does not show the predicted carboxyl-terminal U2AF homology domain in solution, suggesting that the folding and stability of such a domain in MAN1 depend upon binding to an unidentified partner. Modeling the complex between DNA and the winged helix domain shows that the regions involved in DNA binding are essentially distinct from those reported to be involved in Smad binding. This suggests that MAN1 binds simultaneously to R-Smads and their targeted DNA sequences.

Received for publication, March 1, 2006 , and in revised form, April 7, 2006.

The atomic coordinates and structure factors (code 2CH0) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The chemical shift assignments reported here have been deposited in the BioMagRes-Bank Database under accession number 6919.

^* 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 Supported by Grants 8699, 9513, and 11591 from Association Française contre les Myopathies.

² Present address: United Biomedical, Inc., 25 Davids Dr., Hauppauge, NY 11788.

³ Supported by Grant MDA3711 from the Muscular Dystrophy Association.

⁴ To whom correspondence should be addressed. Tel.: 33-1-69-08-30-26; Fax: 33-1-69-08-90-71; E-mail: szinn{at}cea.fr.

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