Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Zhongguancun North First Street 2, Beijing 100190, PR China; University of Chinese Academy of Sciences, Yuquan Road 19(A), Shijingshan District 100049, Beijing, PR China.
Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Zhongguancun North First Street 2, Beijing 100190, PR China.
Biochim Biophys Acta Gen Subj. 2019 Jan;1863(1):31-38. doi: 10.1016/j.bbagen.2018.09.022. Epub 2018 Sep 29.
G-quadruplex has been viewed as a promising therapeutic target in oncology due to its potentially important roles in physiological and pathological processes. Emerging evidence suggests that the biological functions of G-quadruplexes are closely related to the binding of some proteins. Insulin-like growth factor type I (IGF-1), as a significant modulator of cell growth and development, may serve as a quadruplex-binding protein.
The binding affinity and selectivity of IGF-1 to different DNA motifs in solution were measured by using fluorescence spectroscopy, Surface Plasmon Resonance (SPR), and force-induced remnant magnetization (FIRM). The effects of IGF-1 on the formation and stability of G-quadruplex structures were evaluated by circular dichroism (CD) and melting fluorescence resonance energy transfer (FRET) spectroscopy. The influence of quadruplex-specific ligands on the binding of G-quadruplexes with IGF-1 was determined by FIRM.
IGF-1 shows a binding specificity for G-quadruplex structures, especially the G-quadruplex structure with a parallel topology. The quadruplex-specific ligands TMPyP4 and PDS (Pyridostatin) can inhibit the interaction between G-quadruplexes and proteins.
IGF-1 is demonstrated to selectively bind with G-quadruplex structures. The use of quadruplex-interactive ligands could modulate the binding of IGF-1 to G-quadruplexes.
This study provides us with a new perspective to understand the possible physiological relationship between IGF-1 and G-quadruplexes and also conveys a strategy to regulate the interaction between G-quadruplex DNA and proteins.
由于其在生理和病理过程中可能具有重要作用，G-四链体已被视为肿瘤学中一种有前途的治疗靶点。新出现的证据表明，G-四链体的生物学功能与其与某些蛋白质的结合密切相关。胰岛素样生长因子 I（IGF-1）作为细胞生长和发育的重要调节剂，可能是一种四链体结合蛋白。
通过荧光光谱法、表面等离子体共振（SPR）和力诱导剩余磁化（FIRM）测量 IGF-1 在溶液中与不同 DNA 基序的结合亲和力和选择性。通过圆二色性（CD）和熔解荧光共振能量转移（FRET）光谱评估 IGF-1 对 G-四链体结构形成和稳定性的影响。通过 FIRM 确定四链体特异性配体对 G-四链体与 IGF-1 结合的影响。
IGF-1 对 G-四链体结构具有结合特异性，尤其是具有平行拓扑结构的 G-四链体结构。四链体特异性配体 TMPyP4 和 PDS（吡咯并嘧啶）可以抑制 G-四链体与蛋白质之间的相互作用。
IGF-1 被证明可选择性结合 G-四链体结构。使用四链体相互作用配体可以调节 IGF-1 与 G-四链体的结合。
这项研究为我们提供了一个新的视角，以了解 IGF-1 和 G-四链体之间可能存在的生理关系，并提供了一种调节 G-四链体 DNA 与蛋白质相互作用的策略。
