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

Gao, Qian; Hua, Jian; Kimura, Rich; Headd, Jeffery J.; Fu, Xin; Chin, Eugene

doi:10.1074/mcp.m300131-mcp200

Cited by 33 publications

(33 citation statements)

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“…This phenylalanine is highly conserved only in STAT-type domains. 17 To investigate how these structural features are related to known SH2 domain structures, we compared the new structure to known SH2 domain structures, including 32 of the Src-type family and four of the STAT-type (Supplementary Data Table S1). Whereas the βE-βF motif is found only in the Src-type subfamily 17 , helix αL is a feature that occurs adjacent to several SH2 domains of both subfamilies, 22 and might be related to a preceding linker domain, as first observed in STAT proteins (Fig.…”

Section: Unique Fold Of the Spt6 Sh2 Domainmentioning

confidence: 99%

“…17 The amino acid sequences of the proteins were downloaded from Swiss-Prot/TrEMBL. 54 The corresponding SH2 domains were predicted by SMART database, 55 and aligned with ProbCons.…”

Section: Phylogenetic Analysismentioning

confidence: 99%

“…16 SH2 domains can be divided into two structural subfamilies: the Src-type and the STATtype subfamilies. 17 Whereas both families of domains share a central fold, the Src-type domains contain an extra β-sheet (βE-βF motif) that participates in the read-out of residues C-terminal to the phosphotyrosine, 16 and the STAT-type domains show an extended helical structure at their Cterminus (αB' and αB). Phosphorylated peptides bind two pockets on the SH2 domain surface, one that recognizes the phosphorylated tyrosine side chain, and one that contacts residues C-terminal of the phosphotyrosine, generally at register +3.…”

Section: Introductionmentioning

confidence: 99%

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Structure and in Vivo Requirement of the Yeast Spt6 SH2 Domain

Dengl

Mayer

Sun

et al. 2009

Journal of Molecular Biology

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During transcription elongation through chromatin, the Ser2-phosphorylated C-terminal repeat domain of RNA polymerase II binds the C-terminal Src homology 2 (SH2) domain of the nucleosome re-assembly factor Spt6. This SH2 domain is unusual in its specificity to bind phosphoserine, rather than phosphotyrosine and because it is the only SH2 domain in the yeast genome. Here, we report the high-resolution crystal structure of the SH2 domain from Candida glabrata Spt6. The structure combines features from both structural subfamilies of SH2 domains, suggesting it resembles a common ancestor of all SH2 domains. Two conserved surface pockets deviate from those of canonical SH2 domains, and may explain the unusual phosphoserine specificity. Differential gene expression analysis reveals that the SH2 domain is required for normal expression of a subset of yeast genes, and is consistent with multiple functions of Spt6 in chromatin transcription.

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Section: Unique Fold Of the Spt6 Sh2 Domainmentioning

confidence: 99%

“…17 The amino acid sequences of the proteins were downloaded from Swiss-Prot/TrEMBL. 54 The corresponding SH2 domains were predicted by SMART database, 55 and aligned with ProbCons.…”

Section: Phylogenetic Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure and in Vivo Requirement of the Yeast Spt6 SH2 Domain

Dengl

Mayer

Sun

et al. 2009

Journal of Molecular Biology

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“…Protozoan cellular slime mould, Dictyostelium discoideum, possesses functional homologs of the metazoan STAT genes, Dd-STATa-d (Kawata et al, 1997;Fukuzawa et al, 2001;Zhukovskaya et al, 2004;Gao et al, 2004). The Dd-STATa'null strain has defects in both chemotactic cell movements during the aggregation stage and morphogenesis during late development, and the latter defect leads to a failure of culmination (Mohanty et al, 1999).…”

Section: Abstract: Stat Transcription Factor Zinc Transporter Cellmentioning

confidence: 99%

Expression of zinc transporter family genes in Dictyostelium

Sunaga

Monna²,

Shimada

et al. 2008

Int. J. Dev. Biol.

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KEY WORDS: STAT transcription factor, zinc transporter, cell differentiation, DictyosteliumThe JAK/STAT signaling pathways are induced by cytokines and growth factors and play indispensable roles in controlling the immune system, cell fate determination, and cell proliferation in an evolutionarily conserved manner (Darnell, 1997;O'Shea et al., 2002;Rawlings et al., 2004). Protozoan cellular slime mould, Dictyostelium discoideum, possesses functional homologs of the metazoan STAT genes, Dd-STATa-d (Kawata et al., 1997;Fukuzawa et al., 2001;Zhukovskaya et al., 2004;Gao et al., 2004). The Dd-STATa'null strain has defects in both chemotactic cell movements during the aggregation stage and morphogenesis during late development, and the latter defect leads to a failure of culmination (Mohanty et al., 1999). Thus, Dd-STATa is necessary for the entry into culmination that accompanies proper conversion of prestalk cells into stalk cells.In Dictyostelium, the conversion of isolated prestalk cells into stalk cells in vitro is enhanced by zinc ions in the presence of DIF-1, a differentiation-inducing factor (Kubohara and Okamoto, 1994;Kubohara, 1995). This observation indicates that exogenous zinc ions may have an important role in stalk differentiation, although the mechanism of zinc action remains unclear. STAT3 controls EMT (epithelial-mesenchymal transition) through the LIV-1 protein during zebrafish gastrulation (Yamashita et al., 2004). STAT3 is activated in the organizer region and'activates transcription of the LIV-1 gene, which encodes a zinc transporter protein (McClelland et al., 1998). LIV-1 induces nuclear transition of the zinc finger protein Snail, which is a main regulator of EMT and is Int. J. Dev. Biol. 52: 377-381 (2008) doi: 10.1387/ijdb.072389ns (Batlle et al., 2000;Cano et al., 2000). Because the Dd-STATa null strain lacks an organizer-like activity, if LIV-1-related molecules are present in Dictyostelium, then they could be regulated by Dd-STATa and may have crucial roles during fruiting body formation.There are two zinc transporter families in eukaryotes, the CDF (Cation Diffusion Family) and the ZIP (Zrt, Irt-like Proteins) family, the latter family includes LZT (LIV-1 subfamily of ZIP zinc Transporters). While CDF is responsible for zinc transport from the cytoplasm to either intracellular organelles or extracellular spaces, the ZIP family is important for transferring zinc from the extracellular space into the cytoplasm (Taylor and Nicholson, 2003;Liuzzi and Cousins, 2004). The ZIP transporter family consists of four subfamilies: I, II, gufA, and LZT (Gaither and Eide, 2001). The LZT subfamily is distinguished from the other ZIP subfamilies by the presence of the HEXPHEXGD motif in the fifth transmembrane region. This motif is less conserved in other zinc transporter proteins (Taylor and Nicholson, 2003).To identify putative zinc transporters in Dictyostelium, we searched the amino acid sequences of Zrt, Irt, and ZIP proteins (ZIP subfamilies I and II), LIV-1 and KE4 proteins (LZT subfamily), ...

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“…2B). This atypical SH2 domain serves as a reminder of the diversity of the SH2 domain family, which may have further unknown members that can only be recognized by secondary or tertiary structural analysis [104].…”

Section: Cbl: Inhibitor Of Active Ptksmentioning

confidence: 99%

Probing the Tyrosine Phosphorylation State in Breast Cancer by Src Homology 2 Domain Binding

Mayer¹

2004

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Pubhc reporting burden for Ms collection of information is estimated to average 1 hour per response, Including the lime for reviewing instructions, searching existing data sources gathering and maintaininn the data neededI andcompletingland renewing this collection of information. Send comments regarding this burden estimate or any other asped of this collection of InfoirnaBorf iffsSÄto" educing this burden to Washington Headquarters AUTHOR(S)Bruce J. Mayer PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)University Abstract (Maximum 200 Words) (abstract should contain no proprietary or confidential information)Improved molecular diagnostic methods that can classify tumors and predict their response to therapy have enormous potential to improve the effectiveness breast cancer treatments. The overall goal of this project is to develop a novel molecular diagnostic method, i: termed SH2 profiling, that can classify cell samples based on their global protein tyrosine phosphorylation state. The first aim is to use an existing SH2 profiling method, based on far-Western blotting, to analyze fresh surgical breast cancer samples. The second aim is to o develop a more high-throughput quantitative reversed-phase SH2 profiling format, and test its usefulness in classifying breast cancer samples. The third aim is to develop histochemical SH2 profiling methods that can be used to analyze archived, formalin-fixed tissue sections, and perform pilot retrospective studies to determine whether SH2 binding patterns have potential prognostic value. In the past year we have made great progress in developing the reversed-phase array and histochemical SH2 profiling formats, and results suggest that these quantitative methods will be useful in classifying breast cancer samples. In the coming year, once HSRRB approval for use of human samples is secured, we will begin to apply these new methods to the analysis of actual breast cancer specimens. SUBJECT TERMS Conclusions 9References 10 Appendices 10-93Mayer, B.J. INTRODUCTIONThe focus is this study is to test whether a novel molecular diagnostic approach, SH2 profiling, can serve as a useful prognostic tool to classify breast cancer. SH2 domains are small protein modules that bind specifically to tyrosine phosphorylated peptides. These domains play an important role in normal signal transduction, mediating the formation of multiprotein complexes in response to changes in tyrosine phosphorylation [1,2]. There are ~116 SH2 domains in the human genome, and different SH2 domains recognize different tyrosine phosphorylated proteins. SH2 profiling is a method in which a battery SH2 domain probes is used to provide a snapshot of the global state of tyrosine phosphorylation in a cell sample [3,4]. Different breast cancers are likely to have different patterns of tyrosine phosphorylation, reflecting differences in the signal transduction pathways active in the tumor, and thus SH2 profiling has the potential to provide a biologically relevant means to classify these tumors. In this project we prop...

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

Cited by 33 publications

References 37 publications

Structure and in Vivo Requirement of the Yeast Spt6 SH2 Domain

Structure and in Vivo Requirement of the Yeast Spt6 SH2 Domain

Expression of zinc transporter family genes in Dictyostelium

Probing the Tyrosine Phosphorylation State in Breast Cancer by Src Homology 2 Domain Binding

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