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核仁对泛素连接酶动力学的调控

Regulation of ubiquitin ligase dynamics by the nucleolus.

作者信息

Mekhail Karim, Khacho Mireille, Carrigan Amanda, Hache Robert R J, Gunaratnam Lakshman, Lee Stephen

机构信息

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.

出版信息

J Cell Biol. 2005 Aug 29;170(5):733-44. doi: 10.1083/jcb.200506030.

DOI:10.1083/jcb.200506030
PMID:16129783
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2171338/
Abstract

Cellular pathways relay information through dynamic protein interactions. We have assessed the kinetic properties of the murine double minute protein (MDM2) and von Hippel-Lindau (VHL) ubiquitin ligases in living cells under physiological conditions that alter the stability of their respective p53 and hypoxia-inducible factor substrates. Photobleaching experiments reveal that MDM2 and VHL are highly mobile proteins in settings where their substrates are efficiently degraded. The nucleolar architecture converts MDM2 and VHL to a static state in response to regulatory cues that are associated with substrate stability. After signal termination, the nucleolus is able to rapidly release these proteins from static detention, thereby restoring their high mobility profiles. A protein surface region of VHL's beta-sheet domain was identified as a discrete [H+]-responsive nucleolar detention signal that targets the VHL/Cullin-2 ubiquitin ligase complex to nucleoli in response to physiological fluctuations in environmental pH. Data shown here provide the first evidence that cells have evolved a mechanism to regulate molecular networks by reversibly switching proteins between a mobile and static state.

摘要

细胞通路通过动态蛋白质相互作用传递信息。我们已经评估了小鼠双微体蛋白（MDM2）和冯·希佩尔-林道（VHL）泛素连接酶在生理条件下活细胞中的动力学特性，这些生理条件会改变它们各自的p53和缺氧诱导因子底物的稳定性。光漂白实验表明，在其底物被有效降解的情况下，MDM2和VHL是高度可移动的蛋白质。核仁结构会根据与底物稳定性相关的调节信号将MDM2和VHL转变为静态状态。信号终止后，核仁能够迅速将这些蛋白质从静态滞留中释放出来，从而恢复它们的高移动性特征。VHLβ-折叠结构域的一个蛋白质表面区域被确定为一个离散的[H⁺]响应性核仁滞留信号，该信号会根据环境pH值的生理波动将VHL/Cullin-2泛素连接酶复合物靶向到核仁。此处所示数据提供了首个证据，表明细胞已经进化出一种机制，通过在可移动和静态状态之间可逆地切换蛋白质来调节分子网络。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/9feddb78507a/200506030f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/37eacbc575d4/200506030f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/459a7690d8fc/200506030f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/4e62a0a325db/200506030f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/9e2845c409f0/200506030f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/a6001ab01372/200506030f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/715d3f13db2c/200506030f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/98315de8537f/200506030f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/4cc657522467/200506030f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/2dabaafb0980/200506030f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/9feddb78507a/200506030f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/37eacbc575d4/200506030f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/459a7690d8fc/200506030f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/4e62a0a325db/200506030f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/9e2845c409f0/200506030f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/a6001ab01372/200506030f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/715d3f13db2c/200506030f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/98315de8537f/200506030f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/4cc657522467/200506030f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/2dabaafb0980/200506030f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/2171338/9feddb78507a/200506030f10.jpg

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本文引用的文献

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Function and regulation of cullin-RING ubiquitin ligases.泛素连接酶Cullin-RING的功能与调控
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