Daear Weiam, Mundle Robyn, Sule Kevin, Prenner Elmar J
Department of Biological Sciences, University of Calgary, T2N 1N4 Calgary, Alberta, Canada.
BBA Adv. 2021 Aug 3;1:100021. doi: 10.1016/j.bbadva.2021.100021. eCollection 2021.
This work assessed effects of metal binding on membrane fluidity, liposome size, and lateral organization in biomimetic membranes composed of 1 mol% of selected phosphorylated phosphoinositides in each system. Representative examples of phosphoinositide phosphate, bisphosphate and triphosphate were investigated. These include phosphatidylinositol-(4,5)-bisphosphate, an important signaling lipid constituting a minor component in plasma membranes whereas phosphatidylinositol-(4,5)-bisphosphate clusters support the propagation of secondary messengers in numerous signaling pathways. The high negative charge of phosphoinositides facilitates electrostatic interactions with metals. Lipids are increasingly identified as toxicological targets for divalent metals, which potentially alter lipid packing and domain formation. Exposure to heavy metals, such as lead and cadmium or elevated levels of essential metals, like cobalt, nickel, and manganese, implicated with various toxic effects were investigated. Phosphatidylinositol-(4)-phosphate and phosphatidylinositol-(3,4,5)-triphosphate containing membranes are rigidified by lead, cobalt, and manganese whilst cadmium and nickel enhanced fluidity of membranes containing phosphatidylinositol-(4,5)-bisphosphate. Only cobalt induced liposome aggregation. All metals enhanced lipid clustering in phosphatidylinositol-(3,4,5)-triphosphate systems, cobalt in phosphatidylinositol-(4,5)-bisphosphate systems, while all metals showed limited changes in lateral film organization in phosphatidylinositol-(4)-phosphate matrices. These observed changes are relevant from the biophysical perspective as interference with the spatiotemporal formation of intricate domains composed of important signaling lipids may contribute to metal toxicity.
本研究评估了金属结合对仿生膜中膜流动性、脂质体大小和侧向组织的影响，每个系统中仿生膜由1 mol%的选定磷酸化磷脂酰肌醇组成。研究了磷脂酰肌醇磷酸、双磷酸和三磷酸的代表性实例。这些包括磷脂酰肌醇-（4,5）-双磷酸，这是一种重要的信号脂质，在质膜中构成次要成分，而磷脂酰肌醇-（4,5）-双磷酸簇支持多种信号通路中第二信使的传播。磷脂酰肌醇的高负电荷有利于与金属发生静电相互作用。脂质越来越被认为是二价金属的毒理学靶点，这可能会改变脂质堆积和结构域形成。研究了暴露于重金属（如铅和镉）或必需金属（如钴、镍和锰）水平升高的情况，这些金属与各种毒性作用有关。含磷脂酰肌醇-（4）-磷酸和磷脂酰肌醇-（3,4,5）-三磷酸的膜被铅、钴和锰硬化，而镉和镍增强了含磷脂酰肌醇-（4,5）-双磷酸膜的流动性。只有钴诱导脂质体聚集。所有金属都增强了磷脂酰肌醇-（3,4,5）-三磷酸系统中的脂质聚集，钴增强了磷脂酰肌醇-（4,5）-双磷酸系统中的脂质聚集，而所有金属在磷脂酰肌醇-（4）-磷酸基质中的侧向膜组织变化有限。从生物物理学角度来看，这些观察到的变化是相关的，因为干扰由重要信号脂质组成的复杂结构域的时空形成可能会导致金属毒性。
