How Phosphorylation by PINK1 Remodels the Ubiquitin System: A Perspective from Structure and Dynamics
How Phosphorylation by PINK1 Remodels the Ubiquitin System: A Perspective from Structure and Dynamics
复制标题
PINK1 的磷酸化如何重塑泛素系统：结构和动力学的视角
DOI：
10.1021/acs.biochem.9b00715
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发表时间：
2020-01-14
期刊：
影响因子：
2.9
通讯作者：
Zhang, Wei-Ping
中科院分区：
文献类型：
--
作者：
Tang, Chun;Zhang, Wei-Ping
泛素是细胞内重要的信号蛋白。它通过与底物蛋白的共价连接和与靶蛋白的非共价相互作用发挥作用。泛素也是连接的，并且所得的多聚泛素以增强的特异性多价地识别靶蛋白。泛蛋白和多聚泛蛋白的构象动力学使泛蛋白的功能成为可能，其在时间尺度上跨越超过12个数量级。最近，发现泛素可以被PINK 1在残基S65和T66处磷酸化。只有稀疏的未修饰的泛素，C-末端收缩构象稳定的磷酸化的泛素，并进一步丰富在增加的pH值。三级结构的调制进一步影响的四元排列的泛素亚基在聚泛素。此外，泛素磷酸化抑制许多负责连接和去除多聚泛素的酶的活性，从而重塑多聚泛素的组成和长度。磷酸化改造的多聚泛素可以识别不同的靶蛋白。由于PINK 1和泛素磷酸化水平在某些病理生理条件下上调，重构的泛素系统可能参与细胞命运的分化。
Ubiquitin is an important signaling protein in cells. It functions by covalent attachment to substrate proteins and by noncovalent interactions with target proteins. Ubiquitins are also concatenated, and the resulting polyubiquitins recognize target proteins multivalently with enhanced specificity. The function of ubiquitin is enabled by the conformational dynamics of ubiquitin and polyubiquitins, which spans over 12 orders of magnitude in a time scale. Recently, it was found that ubiquitin can be phosphorylated by PINK1 at residues S65 and T66. Only sparsely populated for the unmodified ubiquitin, a C-terminally retracted conformation is stabilized for phosphorylated ubiquitin and is further enriched at an increasing pH. The modulation of tertiary structure further impacts the quaternary arrangements of ubiquitin subunits in polyubiquitins. Additionally, ubiquitin phosphorylation inhibits the activities of many enzymes responsible for attaching and removing polyubiquitins, thus remodeling the composition and length of polyubiquitins. The phosphorylation-remolded polyubiquitins can then recognize different target proteins. As PINK1 and ubiquitin phosphorylation levels are up-regulated under certain pathophysiological conditions, the remodeled ubiquitin system may be involved in the divergence of cell fate.