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J. Biol. Chem., Vol. 280, Issue 51, 41844-41851, December 23, 2005

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The Conserved Leu-724 Residue Is Required for Both Serine Phosphorylation and Co-activator Recruitment for Stat1-mediated Transcription Activation in Response to Interferon-^*

Wei Sun1, Weifeng Xu, Marylynn Snyder, Wei He, Hao Ho, Lionel B. Ivashkiv¶, and J. Jillian Zhang2

From the Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York 10021, Arthritis and Tissue Degeneration Program, and ^¶Immunology Program, Hospital for Special Surgery, New York, New York 10021

The signal transducer and activator of transcription (STAT) proteins, a family of latent cytoplasmic transcription factors, become activated in response to extracellular ligand binding to cell surface receptors through tyrosine phosphorylation. Concurrently, a serine phosphorylation event in the transcription activation domain (serine 727 for Stat1) occurs. This serine phosphorylation is essential for the maximal transcription activity of Stat1. Here we show that, in addition to the Ser-727 residue and its phosphorylation, the conserved Leu-724 residue is also essential for gene activation mediated by Stat1. When Leu-724 is mutated to Ala, phosphorylation of Stat1 Ser-727 is defective both in vivo and in vitro. Surprisingly, we found a StatL724I mutant that lacks transcription activity despite normal Ser-727 phosphorylation. Further analyses show that Leu-724, as well as the phospho-Ser-727, are essential for the recruitment of the transcription co-activator CBP/p300 to the promoters of Stat1 target genes. Our results demonstrate that the conserved Leu-724 residue is a key residue that controls the maximal transcription activities of Stat1 in IFN- signaling.

Received for publication, May 27, 2005 , and in revised form, September 12, 2005.

^* This work is supported by National Institutes of Health Grant GM61652 and American Heart Association Grant 0455896T (to J. J. Z.). 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 a postdoctoral fellowship from the American Heart Association.

² To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021. Tel.: 212-746-4614; Fax: 212-746-8302; E-mail: jjz2002{at}med.cornell.edu.

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