Department of chemistry, Aligarh Muslim University, Aligarh 202002, U.P., India.
Department of chemistry, Aligarh Muslim University, Aligarh 202002, U.P., India.
Biophys Chem. 2018 Sep;240:50-62. doi: 10.1016/j.bpc.2018.05.006. Epub 2018 May 26.
GDF-5 mediated signal transduction regulating chondrogenesis and skeletogenesis involves three different type-I receptors viz. Act-RI, BMPRIA and BMPRIB. BMPRIA and BMPRIB generally shows temporal and spatial co-expression but some spatially different expression pattern has also been observed. BMPRIA receptor is the key receptor implicated in BMP signalling during osteogenesis and is expressed in osteoblasts during the course of bone formation. However, BMPRIB appears to be primarily expressed in mesenchymal pre-cartilage condensations and also found in differentiated osteoblast and chondrocytes. The extracellular pH affects bone cell function and it is experimentally known that mineralization of bone is affected by shift of pH in cultured osteoblast. Here we report the effect of pH on dynamics of water present at the interface of GDF-5:BMPRIA and GDF-5:BMPRIB and binding interaction energy of these complexes. Water dynamics at different pH was analysed using residence time and hydrogen bond relaxation kinetics. pH influences the interaction energy between GDF-5 and BMPRIA and BMPRIB receptors indicating the electrostatic environment modulating the activity of two receptors. This pH dependence of interaction energy is further supported by similar behaviour of hydrogen bond existence of buried water molecules at the interface. In contrast to this the slow and fast exchanging water molecules do not show similar pH dependence of hydrogen bonding relaxation kinetics. Hence; we conclude that only buried water molecule at the interface influences the protein-protein interaction and the electrostatic environment of the extracellular fluid might decide the specificity of the two receptors.
GDF-5 介导的信号转导调节软骨生成和骨发生涉及三种不同的 I 型受体，即 Act-RI、BMPRIA 和 BMPRIB。BMPRIA 和 BMPRIB 通常表现出时间和空间的共表达，但也观察到一些空间上不同的表达模式。BMPRIA 受体是骨发生过程中 BMP 信号转导中涉及的关键受体，在骨形成过程中表达于成骨细胞中。然而，BMPRIB 似乎主要表达于间质前软骨凝聚物中，也存在于分化的成骨细胞和软骨细胞中。细胞外 pH 值影响骨细胞的功能，实验表明，骨的矿化受培养的成骨细胞中 pH 值变化的影响。在这里，我们报告了 pH 值对 GDF-5:BMPRIA 和 GDF-5:BMPRIB 界面上水的动态以及这些复合物结合相互作用能的影响。使用停留时间和氢键弛豫动力学分析了不同 pH 值下的水动力学。pH 值影响 GDF-5 与 BMPRIA 和 BMPRIB 受体之间的相互作用能，表明静电环境调节两个受体的活性。这种相互作用能的 pH 值依赖性得到了界面上埋藏水分子氢键存在的相似行为的支持。与此相反，慢交换和快交换水分子的氢键弛豫动力学没有表现出相似的 pH 值依赖性。因此，我们得出结论，只有界面处埋藏的水分子会影响蛋白质-蛋白质相互作用，细胞外液的静电环境可能决定两个受体的特异性。
