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Molecular & Cellular Proteomics 3:704-714, 2004.
© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Identification of the Linker-SH2 Domain of STAT as the Origin of the SH2 Domain Using Two-dimensional Structural Alignment^*

Qian Gao^,, Jian Hua^,¶, Rich Kimura^||, Jeffery J. Headd^**, Xin-yuan Fu and Y. Eugene Chin^**,¶¶

From the Whitehead Institute for Biomedical Research, Cambridge, MA 02142; ^|| Section of Molecular and Cellular Biology, University of California, Davis, CA 95616; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510; and ^** Departments of Surgery Science and Molecular Biology, Cell Biology and Biochemistry, Brown University School of Medicine, Providence, RI 02903

The availability of large volumes of genomic sequences presents an unprecedented proteomic challenge to characterize the structure and function of various protein motifs. Primary structural alignment is often unable to accurately identify a given motif due to sequence divergence; however, with the aid of secondary structural prediction for analysis, it becomes feasible to explore protein motifs on a proteome-wide scale. Here we report the use of secondary structural alignment to characterize the Src homology 2 (SH2) domains of both conventional and divergent sequences and divide them into two groups, Src-type and STAT-type. In addition to the basic "ßßß" structure (ßB), the Src-type SH2 domain contains an extra ß-strand (ßE or ßE-ßF motif). Alternatively, the linker domain-conjugated SH2 domain in STAT contains the B` motif. Combining BLAST data from ßB core motif sequences with predicted secondary structural alignment, we have screened for SH2 domains in various eukaryotic model systems including Arabidopsis, Dictyostelium, and Saccharomyces. Two novel genes carrying the linker-SH2 domain of STAT were discovered and subsequently cloned from Arabidopsis. These genes, designated as STAT-type linker-SH2 domain factors (STATL), are found in a wide array of vascular and nonvascular plants, suggesting that the linker-SH2 domain evolved prior to the divergence of plants and animals. Using this approach, we expanded the number of putative SH2 domain-bearing genes in Dictyostelium and comparatively studied the secondary structural profiles of both typical and atypical SH2 domains. Our results indicate that the linker-SH2 domain of the transcription factor STAT is one of the most ancient and fully developed functional domains, serving as a template for the continuing evolution of the SH2 domain essential for phosphotyrosine signal transduction.

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