National Research Council of Italy - Materials Foundry Istituto Officina dei Materiali c/o International School for Advanced Studies, 34136 Trieste, Italy.
Laboratory for Environmental and Life Sciences, University of Nova Gorica, 5000 Nova Gorica, Slovenia.
Proc Natl Acad Sci U S A. 2022 Nov 29;119(48):e2214602119. doi: 10.1073/pnas.2214602119. Epub 2022 Nov 21.
The function of many channels and transporters is enriched by the conformational plasticity of intrinsically disordered regions (IDRs). Copper transporter 1 (Ctr1) is the main entry point for Cu(I) ions in eukaryotes and contains IDRs both at its N-terminal (Nterm) and C-terminal ends. The former delivers copper ions from the extracellular matrix to the selectivity filter in the Ctr1 lumen. However, the molecular mechanism of this process remains elusive due to Nterm's disordered nature. Here, we combine advanced molecular dynamics simulations and circular dichroism experiments to show that Cu(I) ions and a lipidic environment drive the insertion of the Nterm into the Ctr1 selectivity filter, causing its opening. Through a lipid-aided conformational switch of one of the transmembrane helices, the conformational change of the selectivity filter propagates down to the cytosolic gate of Ctr1. Taken together, our results elucidate how conformational variability of IDRs modulates ion transport.
许多通道和转运蛋白的功能通过无序区域（IDR）的构象可塑性得到丰富。铜转运蛋白 1（Ctr1）是真核生物中 Cu（I）离子的主要进入点，其 N 端（Nterm）和 C 端都含有 IDR。前者将铜离子从细胞外基质输送到 Ctr1 腔中的选择性过滤器。然而，由于 Nterm 的无序性质，该过程的分子机制仍然难以捉摸。在这里，我们结合先进的分子动力学模拟和圆二色性实验表明，Cu（I）离子和脂质环境驱动 Nterm 插入 Ctr1 选择性过滤器，导致其打开。通过跨膜螺旋之一的脂质辅助构象开关，选择性过滤器的构象变化向下传播到 Ctr1 的胞质门。总之，我们的结果阐明了 IDR 的构象可变性如何调节离子转运。
