Molecular Determinants of a Regulatory Prolyl Isomerization in the Signal Adapter Protein c-CrkII

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• 作者：Philipp A. M. Schmidpeter ; Franz X. Schmid
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：May 16, 2014
• 年：2014
• 卷：9
• 期：5
• 页码：1145-1152
• 全文大小：415K
• 年卷期：v.9,no.5(May 16, 2014)
• ISSN：1554-8937

文摘

The cellular CT10 regulator of kinase protein (c-CrkII) transmits signals from oncogenic tyrosine kinases to cellular targets. Nuclear magnetic resonance studies had suggested that in chicken c-CrkII a native state prolyl cis鈥?i>trans isomerization is involved in signal propagation. Corresponding evidence for the closely related human c-CrkII was not obtained. Here we analyzed the kinetics of folding and substrate binding of the two homologues and found that cis鈥?i>trans isomerization of Pro238 determines target binding in chicken but not in human c-CrkII. A reciprocal mutational analysis uncovered residues that determine the isomeric state at Pro238 and transmit it to the binding site for downstream target proteins. The transfer of these key residues to human c-CrkII established a regulatory proline switch in this protein, as well. We suggest that Pro238 isomerization extends the lifetime of the signaling-active state of c-CrkII and thereby functions as a long-term molecular storage device.