The Highs and Lows of FBXW7: New Insights into Substrate Affinity in Disease and Development.
The Highs and Lows of FBXW7: New Insights into Substrate Affinity in Disease and Development.
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FBXW7的高潮：对疾病和发育中底物亲和力的新见解。
DOI：
10.3390/cells12172141
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发表时间：
2023-08-24
期刊：
影响因子：
6
通讯作者：
de la Cova, Claire C.
中科院分区：
文献类型：
--
作者：
de la Cova, Claire C.
FBXW 7是细胞周期、细胞信号传导和发育的关键调节因子。FBXW 7是一种高度保守的F-box蛋白，也是SKP 1-Cullin-F-box（SCF）复合物的组成部分，在Cullin-RING E3泛素连接酶中作为识别亚基发挥作用，负责泛素化底物蛋白并靶向它们进行蛋白酶体介导的降解。在人类细胞中，FBXW 7促进大量底物蛋白的降解，包括许多影响疾病的蛋白，如NOTCH 1，细胞周期蛋白E，MYC和BRAF。研究的一个中心焦点是了解FBXW 7所表现出的精致底物特异性的分子机制。最近的工作对FBXW 7如何与高亲和力和低亲和力底物发生物理相互作用有了更清楚的了解。我们回顾了新的发现，这些发现为人类癌症中发现的FBXW 7“热点”错义突变的后果提供了见解。最后，我们讨论了FBXW 7-底物相互作用，以及负责底物磷酸化的激酶，如何在C. elegans发育
FBXW7 is a critical regulator of cell cycle, cell signaling, and development. A highly conserved F-box protein and component of the SKP1–Cullin–F-box (SCF) complex, FBXW7 functions as a recognition subunit within a Cullin–RING E3 ubiquitin ligase responsible for ubiquitinating substrate proteins and targeting them for proteasome-mediated degradation. In human cells, FBXW7 promotes degradation of a large number of substrate proteins, including many that impact disease, such as NOTCH1, Cyclin E, MYC, and BRAF. A central focus for investigation has been to understand the molecular mechanisms that allow the exquisite substrate specificity exhibited by FBXW7. Recent work has produced a clearer understanding of how FBXW7 physically interacts with both high-affinity and low-affinity substrates. We review new findings that provide insights into the consequences of “hotspot” missense mutations of FBXW7 that are found in human cancers. Finally, we discuss how the FBXW7–substrate interaction, and the kinases responsible for substrate phosphorylation, contribute to patterned protein degradation in C. elegans development.
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