Effect of the SH3-SH2 domain linker sequence on the structure of Hck kinase |
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Authors: | Heike Meiselbach Heinrich Sticht |
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Institution: | 1.Bioinformatik, Institut für Biochemie,Friedrich-Alexander-Universit?t,Erlangen-Nürnberg,Germany |
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Abstract: | The coordination of activity in biological systems requires the existence of different signal transduction pathways that interact
with one another and must be precisely regulated. The Src-family tyrosine kinases, which are found in many signaling pathways,
differ in their physiological function despite their high overall structural similarity. In this context, the differences
in the SH3-SH2 domain linkers might play a role for differential regulation, but the structural consequences of linker sequence
remain poorly understood. We have therefore performed comparative molecular dynamics simulations of wildtype Hck and of a
mutant Hck in which the SH3-SH2 domain linker is replaced by the corresponding sequence from the homologous kinase Lck. These
simulations reveal that linker replacement not only affects the orientation of the SH3 domain itself, but also leads to an
alternative conformation of the activation segment in the Hck kinase domain. The sequence of the SH3-SH2 domain linker thus
exerts a remote effect on the active site geometry and might therefore play a role in modulating the structure of the inactive
kinase or in fine-tuning the activation process itself. |
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