Hager Anastasia, Wu Mingxuan, Wang Huanchen, Brown Nathaniel W, Shears Stephen B, Veiga Nicolás, Fiedler Dorothea
Department of Chemistry, Princeton University, Washington Rd., Princeton, New Jersey, 08544, USA.
Inositol Signaling Group, National Institutes of Health, Research Triangle Park, North Carolina, 27709, USA.
Chemistry. 2016 Aug 22;22(35):12406-14. doi: 10.1002/chem.201601754. Epub 2016 Jul 27.
The inositol pyrophosphate messengers (PP-InsPs) are emerging as an important class of cellular regulators. These molecules have been linked to numerous biological processes, including insulin secretion and cancer cell migration, but how they trigger such a wide range of cellular responses has remained unanswered in many cases. Here, we show that the PP-InsPs exhibit complex speciation behaviour and propose that a unique conformational switching mechanism could contribute to their multifunctional effects. We synthesised non-hydrolysable bisphosphonate analogues and crystallised the analogues in complex with mammalian PPIP5K2 kinase. Subsequently, the bisphosphonate analogues were used to investigate the protonation sequence, metal-coordination properties, and conformation in solution. Remarkably, the presence of potassium and magnesium ions enabled the analogues to adopt two different conformations near physiological pH. Understanding how the intrinsic chemical properties of the PP-InsPs can contribute to their complex signalling outputs will be essential to elucidate their regulatory functions.
肌醇焦磷酸信使分子（PP-InsPs）正逐渐成为一类重要的细胞调节因子。这些分子与众多生物学过程相关联，包括胰岛素分泌和癌细胞迁移，但在许多情况下，它们如何引发如此广泛的细胞反应仍未得到解答。在此，我们表明PP-InsPs表现出复杂的物种形成行为，并提出一种独特的构象转换机制可能有助于它们的多功能效应。我们合成了不可水解的双膦酸盐类似物，并将其与哺乳动物PPIP5K2激酶形成复合物进行结晶。随后，使用双膦酸盐类似物研究溶液中的质子化序列、金属配位性质和构象。值得注意的是，钾离子和镁离子的存在使类似物在生理pH值附近能够采取两种不同的构象。了解PP-InsPs的内在化学性质如何有助于其复杂的信号输出对于阐明其调节功能至关重要。
