Josephine C. Ferreon*, Hai Minh Ta, Hyosuk Yun, Kyoung-Jae Choi, My Diem Quan, Phoebe S. Tsoi, Choel Kim, Chul Won Lee* and Allan Chris M. Ferreon*,
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引用次数: 0
摘要
NANOG 蛋白水平与干细胞多能性相关。NANOG浓度不断波动,NANOG水平低会导致细胞自发分化。以前的文献表明,磷酸化依赖性脯氨酰异构酶 Pin1 是 NANOG 稳定的关键角色。在这里,我们利用核磁共振光谱研究了 Pin1 与 NANOG 非结构化 N 端结构域的分子相互作用,该结构域包含一个带有两个磷酸化位点的 PEST 序列。NANOG PEST 肽的磷酸化增加了与 Pin1 的亲和力。通过系统地增加顺式 PEST 构象的数量,我们发现肽与 Pin1 的脯氨酰异构酶结构域(PPIase)结合得更紧密。两个 PEST 位点的磷酸化和顺式 Pro 增强分别导致 NANOG 与 Pin1 WW 结构域和 PPIase 结构域的结合增加了 5-10 倍。顺式填充的NANOG PEST肽可作为潜在的抑制剂,破坏癌症干细胞中依赖于Pin1的NANOG稳定。
NANOG protein levels correlate with stem cell pluripotency. NANOG concentrations fluctuate constantly with low NANOG levels leading to spontaneous cell differentiation. Previous literature implicated Pin1, a phosphorylation-dependent prolyl isomerase, as a key player in NANOG stabilization. Here, using NMR spectroscopy, we investigate the molecular interactions of Pin1 with the NANOG unstructured N-terminal domain that contains a PEST sequence with two phosphorylation sites. Phosphorylation of NANOG PEST peptides increases affinity to Pin1. By systematically increasing the amount of cis PEST conformers, we show that the peptides bind tighter to the prolyl isomerase domain (PPIase) of Pin1. Phosphorylation and cis Pro enhancement at both PEST sites lead to a 5–10-fold increase in NANOG binding to the Pin1 WW domain and PPIase domain, respectively. The cis-populated NANOG PEST peptides can be potential inhibitors for disrupting Pin1-dependent NANOG stabilization in cancer stem cells.
期刊介绍:
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