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J. Biol. Chem., Vol. 279, Issue 18, 18967-18973, April 30, 2004

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Structural Requirements for Signal Transducer and Activator of Transcription 3 Binding to Phosphotyrosine Ligands Containing the YXXQ Motif^*

Huang Shao, Xuejun Xu, Mary-Ann A. Mastrangelo, Naijie Jing, Richard G. Cook, Glen B. Legge¶, and David J. Tweardy||

From the Section of Infectious Diseases, Department of Medicine, the Department of Immunology, Baylor College of Medicine, Houston, Texas 77030 and the ^¶Department of Biochemistry, University of Houston, Houston, Texas 77204-5001

Stat3 is an Src homology (SH)2-containing protein constitutively activated in a wide variety of human cancers following its recruitment to YXXQ-containing motifs, which results in resistance to apoptosis. Despite resolution of the crystal structure of Stat3 homodimer bound to DNA, the structural basis for the unique specificity of Stat3 SH2 for YXXQ-containing phosphopeptides remains unresolved. We tested three models of this interaction based on computational analysis of available structures and sequence alignments, two of which assumed an extended peptide configuration and one in which the peptide had a -turn. By using peptide immunoblot affinity assays and mirror resonance affinity analysis, we demonstrated that only phosphotyrosine (Tyr(P)) peptides containing +3 Gln (not Leu, Met, Glu, or Arg) bound to wild type Stat3. Examination of a series of wild type and mutant Stat3 proteins demonstrated loss of binding to pYXXQ-containing peptides only in Stat3 mutated at Lys-591 or Arg-609, whose side chains interact with the Tyr(P) residue, and Stat3 mutated at Glu-638, whose amide hydrogen bonds with oxygen within the +3 Gln side chain when the peptide ligand assumes a -turn. These findings support a model for Stat3 SH2 interactions that could form the basis for anticancer drugs that specifically target Stat3.

Received for publication, December 22, 2003 , and in revised form, February 2, 2004.

^* This work was supported in part by National Institutes of Health R01 Grant CA86430. 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.

^|| To whom correspondence should be addressed: Section of Infectious Diseases, Baylor College of Medicine, One Baylor Plaza, BCM 286, Rm. 1319, Houston, TX 77030. Tel.: 713-798-8918; Fax: 713-798-8948; E-mail: dtweardy{at}bcm.tmc.edu.

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