Structural insights into calcium-bound S100P and the V domain of the RAGE complex.
Structural insights into calcium-bound S100P and the V domain of the RAGE complex.
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DOI：
10.1371/journal.pone.0103947
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Yu C
中科院分区：
文献类型：
--
作者：
Penumutchu SR;Chou RH;Yu C
S100P蛋白是S100钙结合蛋白家族中的一员，具有细胞内和细胞外功能。细胞外S100P与细胞表面晚期糖基化终末产物受体(RAGE)结合，激活其下游信号级联以抑制肿瘤生长、耐药和转移。防止这种S100P-RAGE复合体的形成是治疗各种疾病的有效策略。尽管它很重要，但S100P-RAGE复合体的详细结构特征尚未报道。在本研究中，我们报道了S100P优先与RAGE的V结构域结合。此外，我们还利用多种生物物理技术，包括恒温滴定量热法(ITC)、荧光光谱、多维核磁共振光谱、功能分析和定点突变，研究了RAGE V结构域与钙结合的S100P之间的相互作用。RAGE的V结构域与钙离子结合的S100P之间的结合在微摩尔范围内(∼的Kd为6µM)。核磁共振数据驱动的黑线鳕建模揭示了相互作用产生S100P-RAGE V结构域复合体的异四聚体模型的假定位点。我们对所提出的蛋白质-蛋白质复合体的空间结构信息的研究具有药学意义，并将为预防RAGE相关的多种疾病的药物开发做出重要贡献。
The S100P protein is a member of the S100 family of calcium-binding proteins and possesses both intracellular and extracellular functions. Extracellular S100P binds to the cell surface receptor for advanced glycation end products (RAGE) and activates its downstream signaling cascade to meditate tumor growth, drug resistance and metastasis. Preventing the formation of this S100P-RAGE complex is an effective strategy to treat various disease conditions. Despite its importance, the detailed structural characterization of the S100P-RAGE complex has not yet been reported. In this study, we report that S100P preferentially binds to the V domain of RAGE. Furthermore, we characterized the interactions between the RAGE V domain and Ca2+-bound S100P using various biophysical techniques, including isothermal titration calorimetry (ITC), fluorescence spectroscopy, multidimensional NMR spectroscopy, functional assays and site-directed mutagenesis. The entropy-driven binding between the V domain of RAGE and Ca+2-bound S100P was found to lie in the micromolar range (Kd of ∼6 µM). NMR data-driven HADDOCK modeling revealed the putative sites that interact to yield a proposed heterotetrameric model of the S100P-RAGE V domain complex. Our study on the spatial structural information of the proposed protein-protein complex has pharmaceutical relevance and will significantly contribute toward drug development for the prevention of RAGE-related multifarious diseases.
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影响因子：
3.9
作者：
Fuentes, Maren K.;Nigavekar, Shraddha S.;Huang, Emina H.
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0501459102
发表时间：
2005-03-29
影响因子：
11.1
作者：
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通讯作者：
Fersht, AR
影响因子：
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作者：
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通讯作者：
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