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J. Biol. Chem., Vol. 280, Issue 49, 40782-40787, December 9, 2005

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Structure of the Unphosphorylated STAT5a Dimer^*

Dante Neculai12, Ana Mirela Neculai12, Sophie Verrier2, Kenneth Straub¶, Klaus Klumpp¶, Edith Pfitzner||, and Stefan Becker23

From the Department for NMR-based Structural Biology and Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany, ^¶Roche Palo Alto LLC, Palo Alto, California 94304, and ^||Georg-Speyer-Haus Institute for Biomedical Research, Paul Ehrlich Strasse 42-44, 60596 Frankfurt, Germany

STAT proteins have the function of signaling from the cell membrane into the nucleus, where they regulate gene transcription. Latent mammalian STAT proteins can form dimers in the cytoplasm even before receptor-mediated activation by specific tyrosine phosphorylation. Here we describe the 3.21-Å crystal structure of an unphosphorylated STAT5a homodimer lacking the N-terminal domain as well as the C-terminal transactivation domain. The overall structure of this fragment is very similar to phosphorylated STATs. However, important differences exist in the dimerization mode. Although the interface between phosphorylated STATs is mediated by their Src-homology 2 domains, the unphosphorylated STAT5a fragment dimerizes in a completely different manner via interactions between their -barrel and four-helix bundle domains. The STAT4 N-terminal domain dimer can be docked onto this STAT5a core fragment dimer based on shape and charge complementarities. The separation of the dimeric arrangement, taking place upon activation and nuclear translocation of STAT5a, is demonstrated by fluorescence resonance energy transfer experiments in living cells.

Received for publication, July 15, 2005 , and in revised form, September 26, 2005.

The atomic coordinates and structure factors (code 1Y1U) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-4.

¹ Both authors contributed equally to this work.

² Supported by the Max-Planck-Gesellschaft and Grants BE2345 and So43/63-1 of the Deutsche Forschungsgemeinschaft.

³ To whom correspondence should be addressed. Tel.: 49-551-201-2222; Fax: 49-551-201-2202; E-mail: sabe{at}nmr.mpibpc.mpg.de.

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