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The biophysical basis of receptor tyrosine kinase ligand functional selectivity: Trk-B case study
Biochemical Journal ( IF 4.4 ) Pub Date : 2020-12-11 , DOI: 10.1042/bcj20200671
Fozia Ahmed 1, 2 , Michael D Paul 2, 3 , Kalina Hristova 1, 2, 3
Affiliation  

Tropomyosin receptor kinase B (Trk-B) belongs to the second largest family of membrane receptors, Receptor Tyrosine Kinases (RTKs). Trk-B is known to interact with three different neurotrophins: Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-4 (NT-4), and Neurotrophin-3 (NT-3). All three neurotrophins are involved in survival and proliferation of neuronal cells, but each induces distinct signaling through Trk-B. We hypothesize that the different biological effects correlate with differences in the interactions between the Trk-B receptors, when bound to different ligands, in the plasma membrane. To test this hypothesis, we use quantitative FRET to characterize Trk-B dimerization in response to NT-3 and NT-4 in live cells, and compare it to the previously published data for Trk-B in the absence and presence of BDNF. Our study reveals that the distinct Trk-B signaling outcomes are underpinned by both different configurations and different stabilities of the three ligand-bound Trk-B dimers in the plasma membrane.

中文翻译:

受体酪氨酸激酶配体功能选择性的生物物理学基础:Trk-B 案例研究

原肌球蛋白受体激酶 B (Trk-B) 属于第二大膜受体家族,受体酪氨酸激酶 (RTK)。已知 Trk-B 与三种不同的神经营养因子相互作用:脑源性神经营养因子 (BDNF)、神经营养因子-4 (NT-4) 和神经营养因子-3 (NT-3)。所有三种神经营养因子都参与神经元细胞的存活和增殖,但每种都通过 Trk-B 诱导不同的信号传导。我们假设不同的生物学效应与质膜中 Trk-B 受体在与不同配体结合时相互作用的差异有关。为了验证这一假设,我们使用定量 FRET 来表征活细胞中响应 NT-3 和 NT-4 的 Trk-B 二聚化,并将其与先前公布的在 BDNF 不存在和存在下的 Trk-B 数据进行比较。
更新日期:2020-12-03
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