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Cells regulate metabolic pathways by rigidly locking enzymes in the nucleolus, report Mekhail et al. on page 733. Two ubiquitin ligase enzymes bind in the nucleolus in response to signals that block their activity.6 K: N* r. G6 w* y# d) n. \; X! R' k
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Ubiquitin tagging alters protein fates, often marking substrates for degradation. Regulation of the process occurs at the level of the ubiquitin ligases, called E3s, which facilitate the transfer of ubiquitin from a conjugating enzyme to the target protein. Several E3 proteins aggregate in the nucleolus in response to inhibitory signals. The new results show that two different E3 enzymes, MDM2 and von Hippel-Lindau tumor suppressor (VHL), become immobilized in the structure and probably bind nucleolar scaffold proteins.; i4 b% h! @0 `. @: p
8 B q- v" ?: J8 [4 O: }3 sIn the presence of oxygen, VHL tags the hypoxia-inducible factor (HIF), causing its degradation. The authors identified a domain within VHL that detects increased acidity, such as occurs during hypoxia, and somehow induces VHL to move to the nucleolus from the cytoplasm and nucleoplasm, where it normally resides.+ A; [. |3 o' ^# S; N/ d
* X2 a( |% {$ V, @: a+ ?% E" TAlthough nucleolar proteins involved in ribosome synthesis move in and out of the structure constantly, the authors saw that VHL was static in the nucleolus, based on FRAP, FLIP, and heterokaryon experiments. Upon neutralization of the culture medium, VHL was released from the nucleolus and resumed its dynamic lifestyle.1 [2 j7 W2 L0 U0 e1 Q( a0 i
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MDM2, an E3 that induces the degradation of the p53 tumor suppressor protein, also became fixed in the nucleolus in response to actinomycin-D treatment, which is known to block p53 ubiquitylation.The authors propose that such nucleolar sequestration, and more generally the concept of switching proteins between a mobile and static state, is likely to be a commonly used mechanism for regulating enzyme reactions. The hypothesis is boosted by preliminary experiments, which indicate that numerous proteins have domains similar to the one that directs VHL's nucleolar targeting.(Acidity, as during hypoxia, targets VHL ) |
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发表于 2009-3-6 08:59
发表于 2015-5-25 07:18
