NMR characterization of monomeric and oligomeric conformations of human calcitonin and its interaction with EGCG.
NMR characterization of monomeric and oligomeric conformations of human calcitonin and its interaction with EGCG.
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DOI：
10.1016/j.jmb.2011.12.023
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发表时间：
2012-02-10
影响因子：
5.6
通讯作者：
Ramamoorthy, Ayyalusamy
中科院分区：
文献类型：
--
作者：
Huang, Rui;Vivekanandan, Subramanian;Brender, Jeffrey R.;Abe, Yuki;Naito, Akira;Ramamoorthy, Ayyalusamy
降钙素是一种32个残留的肽骑马，以其低钙作用及其抑制骨骼的抑制作用，而降钙素已用于骨质疏松症的治疗，数十年。已经使用NMR光谱进行了研究。 Tyr12和Phe16以一种有利的方式用于分子间π -π堆积，这被认为是肽关联和纤颤的关键相互作用。一维1H NMR实验证实，HCT的低聚涉及1 mM浓度的会议过渡。通过在纤维形成之前防止HCT的初始缔合的HCT形成。 EGCG的环和胡椒的芳香侧链在抑制HCT的原纤维形成中起重要作用。
Calcitonin is a 32-residue peptide hormone known for its hypocalcemic effect and its inhibition of bone resorption. While calcitonin has been used in therapy for osteoporosis and Paget's disease for decades, human calcitonin (hCT) forms fibrils in aqueous solution that limit its therapeutic application. The molecular mechanism of fiber formation by calcitonin is not well understood. Here, high-resolution structures of hCT at concentrations of 0.3 mM and 1 mM have been investigated using NMR spectroscopy. Comparing the structures of hCT at different concentrations, we discovered that the peptide undergoes a conformational transition from an extended to a β-hairpin structure in the process of molecular association. This conformational transition locates the aromatic side chains of Tyr12 and Phe16 in a favorable way for intermolecular π–π stacking, which is proposed to be a crucial interaction for peptide association and fibrillation. One-dimensional 1H NMR experiments confirm that oligomerization of hCT accompanies the conformational transition at 1 mM concentration. The effect of the polyphenol epigallocatechin 3-gallate (EGCG) on hCT fibrillation was also investigated by NMR and electron microscopy, which show that EGCG efficiently inhibits fibril formation of hCT by preventing the initial association of hCT before fiber formation. The NMR experiments also indicate that the interaction between aromatic rings of EGCG and the aromatic side chains of the peptide may play an important role in inhibiting fibril formation of hCT.
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影响因子：
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