Systematic characterization of the specificity of the SH2 domains of cytoplasmic tyrosine kinases

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• 作者：Bing Zhao^a ; ¹ ; Pauline H. Tan^b ; ¹ ; Shawn S.C. Li^a ; ^sli@uwo.ca ; Dehua Pei^b ; ^{pei.3@asc.ohio-state.edu}
• 关键词：Protein kinase ; Cytoplasmic tyrosine kinase (CTK) ; Src homology 2 (SH2) domain ; OBOC ; Support vector machine (SVM) ; Peptide binding
• 刊名：Journal of Proteomics
• 出版年：2013
• 出版时间：9 April, 2013
• 年：2013
• 卷：81
• 期：Complete
• 页码：56-69
• 全文大小：2110 K

文摘

Cytoplasmic tyrosine kinases (CTK) generally contain a Src-homology 2 (SH2) domain, whose role in the CTK family is not fully understood. Here we report the determination of the specificity of 25 CTK SH2 domains by screening one-bead-one-compound (OBOC) peptide libraries. Based on the peptide sequences selected by the SH2 domains, we built Support Vector Machine (SVM) models for the prediction of binding ligands for the SH2 domains. These models yielded support for the progressive phosphorylation model for CTKs in which the overlapping specificity of the CTK SH2 and kinase domains has been proposed to facilitate targeting of the CTK substrates with at least two potential phosphotyrosine (pTyr) sites. We curated 93 CTK substrates with at least two pTyr sites catalyzed by the same CTK, and showed that 71 % of these substrates had at least two pTyr sites predicted to bind a common CTK SH2 domain. More importantly, we found 34 instances where there was at least one pTyr site predicted to be recognized by the SH2 domain of the same CTK, suggesting that the SH2 and kinase domains of the CTKs may cooperate to achieve progressive phosphorylation of a protein substrate.

This article is part of a Special Issue entitled: From protein structures to clinical applications.