期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2005
卷号：102
期号：18
页码：6279-6284
DOI：10.1073/pnas.0501873102
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：{beta} -TrCP, the F-box protein of the SCF{beta}-TrCP ubiquitin ligase (SCF, Skp1/Cul1/F-box protein), recognizes the doubly phosphorylated DSG motif (DpSG{Phi}XpS) in various SCF{beta}-TrCP target proteins. The Cdc25A phosphatase, a key cell-cycle regulator in vertebrate cells, undergoes a rapid ubiquitin-dependent degradation in response to genotoxic stress. {beta}-TrCP binds to the DSG motif of human Cdc25A in a manner dependent on Chk1 and other unknown kinases. However, Xenopus Cdc25A does not have a DSG motif at the corresponding site of human Cdc25A. Here, we report that both Xenopus Cdc25A and human Cdc25A have a previously undescribed nonphosphorylated DDG motif (DDG{Phi}XD) for recognition by {beta}-TrCP. When analyzed by using Xenopus eggs, the binding of {beta}-TrCP to the DDG motif is essential for the Chk1-induced ubiquitination and degradation of Xenopus Cdc25A and also plays a role in the degradation of human Cdc25A. The DDG motif also exists in human Cdc25B phosphatase (another key cell-cycle regulator), binds {beta}-TrCP strongly, and is essential for the ubiquitination and degradation of the (labile) phosphatase in normal conditions. We provide strong evidence that, in both Cdc25A and Cdc25B, the binding (efficiency) of {beta}-TrCP to the DDG motif is regulated by nearby residues, while ubiquitination is regulated by other events in addition to the {beta}-TrCP binding. Finally, our additional data suggest that {beta}-TrCP may recognize nonphosphorylated DDG-like motifs in many other proteins, including X11L (a putative suppressor of {beta}-amyloid production) and hnRNP-U (a pseudosubstrate of SCF{beta}-TrCP).
