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Molecular and Cellular Biology, January 2000, p. 389-401, Vol. 20, No. 1
0270-7306/0/$04.00+0

DNA Binding Site Selection of Dimeric and Tetrameric Stat5 Proteins Reveals a Large Repertoire of Divergent Tetrameric Stat5a Binding Sites

Elisabetta Soldaini,1,dagger Susan John,1 Stefano Moro,2,Dagger Julie Bollenbacher,1 Ulrike Schindler,3 and Warren J. Leonard1,*

Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute,1 and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases,2 National Institutes of Health, Bethesda, Maryland 20892, and Tularik, Inc., South San Francisco, California 940803

Received 8 February 1999/Returned for modification 8 March 1999/Accepted 23 September 1999

We have defined the optimal binding sites for Stat5a and Stat5b homodimers and found that they share similar core TTC(T/C)N(G/A)GAA interferon gamma-activated sequence (GAS) motifs. Stat5a tetramers can bind to tandemly linked GAS motifs, but the binding site selection revealed that tetrameric binding also can be seen with a wide range of nonconsensus motifs, which in many cases did not allow Stat5a binding as a dimer. This indicates a greater degree of flexibility in the DNA sequences that allow binding of Stat5a tetramers than dimers. Indeed, in an oligonucleotide that could bind both dimers and tetramers, it was possible to design mutants that affected dimer binding without affecting tetramer binding. A spacing of 6 bp between the GAS sites was most frequently selected, demonstrating that this distance is favorable for Stat5a tetramer binding. These data provide insights into tetramer formation by Stat5a and indicate that the repertoire of potential binding sites for this transcription factor is broader than expected.

* Corresponding author. Mailing address: Laboratory of Molecular Immunology, Bldg. 10, Rm. 7N252, NHLBI, NIH, Bethesda, MD 20892-1674. Phone: (301) 496-0098. Fax: (301) 402-0971. E-mail: wjl{at}helix.nih.gov.

dagger Present address: IRIS, Chiron Biocine, Via Fiorentina 1, 53100 Siena, Italy.

Dagger Present address: Molecular Modeling Section, Pharmaceutical Science Department, University of Padova, 35100 Padova, Italy.

Molecular and Cellular Biology, January 2000, p. 389-401, Vol. 20, No. 1
0270-7306/0/$04.00+0


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