Binding, Domain Orientation, and Dynamics of the Lck SH3-SH2 Domain Pair and Comparison with Other Src-Family Kinases

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• 作者：Gregor Hofmann ; Kristian Schweimer ; Anke Kiessling ; Edith Hofinger ; Finn Bauer ; Silke Hoffmann ; Paul Rö ; sch ; Iain D. Campbell ; Jö ; rn M. Werner ; and Heinrich Sticht
• 刊名：Biochemistry
• 出版年：2005
• 出版时间：October 4, 2005
• 年：2005
• 卷：44
• 期：39
• 页码：13043 - 13050
• 全文大小：322K
• 年卷期：v.44,no.39(October 4, 2005)
• ISSN：1520-4995

文摘

The catalytic activity of Src-family kinases is regulated by association with its SH3 and SH2domains. Activation requires displacement of intermolecular contacts by SH3/SH2 binding ligands resultingin dissociation of the SH3 and SH2 domains from the kinase domain. To understand the contribution ofthe SH3-SH2 domain pair to this regulatory process, the binding of peptides derived from physiologicallyrelevant SH2 and SH3 interaction partners was studied for Lck and its relative Fyn by NMR spectroscopy.In contrast to Fyn, activating ligands do not induce communication between SH2 and SH3 domains inLck. This can be attributed to the particular properties of the Lck SH3-SH2 linker which is shown to beextremely flexible thus effectively decoupling the behavior of the SH3 and SH2 domains. Measurementson the SH32 tandem from Lck further revealed a relative domain orientation that is distinctly differentfrom that found in the Lck SH32 crystal structure and in other Src kinases. These data suggest that flexibilitybetween SH2 and SH3 domains contributes to the adaptation of Src-family kinases to specific environmentsand distinct functions.