Nemashkalova Ekaterina L, Permyakov Eugene A, Permyakov Sergei E, Litus Ekaterina A
Protein Research Group, Institute for Biological Instrumentation of the Russian Academy of Sciences, Institutskaya Str., 7, Pushchino, Moscow region, Russia, 142290.
Department of Biomedical Engineering, Pushchino State Institute of Natural Sciences, Science av., 3, Pushchino, Moscow region, Russia, 142290.
Biometals. 2017 Jun;30(3):341-353. doi: 10.1007/s10534-017-0010-5. Epub 2017 Mar 16.
Human serum albumin (HSA) is an abundant multiligand carrier protein, linked to progression of Alzheimer's disease (AD). Blood HSA serves as a depot of amyloid β (Aβ) peptide. Aβ peptide-buffering properties of HSA depend on interaction with its ligands. Some of the ligands, namely, linoleic acid (LA), zinc and copper ions are involved into AD progression. To clarify the interplay between LA and metal ion binding to HSA, the dependence of LA binding to HSA on Zn, Cu, Mg and Ca levels and structural consequences of these interactions have been explored. Seven LA molecules are bound per HSA molecule in the absence of the metal ions. Zn binding to HSA causes a loss of one bound LA molecule, while the other metals studied exert an opposite effect (1-2 extra LA molecules are bound). In most cases, the observed effects are not related to the metal-induced changes in HSA quaternary structure. However, the Zn-induced decline in LA capacity of HSA could be due to accumulation of multimeric HSA forms. Opposite to Ca/Mg-binding, Zn or Cu association with HSA induces marked changes in its hydrophobic surface. Overall, the divalent metal ions modulate LA capacity and affinity of HSA to a different extent. LA- and Ca-binding to HSA synergistically support each other. Zn and Cu induce more pronounced changes in hydrophobic surface and quaternary structure of HSA and its LA capacity. A misbalanced metabolism of these ions in AD could modify interactions of HSA with LA, other fatty acids and hydrophobic substances, associated with AD.
人血清白蛋白（HSA）是一种丰富的多配体载体蛋白，与阿尔茨海默病（AD）的进展有关。血液中的HSA作为淀粉样β（Aβ）肽的储存库。HSA的Aβ肽缓冲特性取决于其与配体的相互作用。其中一些配体，即亚油酸（LA）、锌离子和铜离子，参与了AD的进展。为了阐明LA与金属离子结合到HSA之间的相互作用，研究了LA与HSA结合对锌、铜、镁和钙水平的依赖性以及这些相互作用的结构后果。在没有金属离子的情况下，每个HSA分子结合7个LA分子。锌与HSA结合会导致一个结合的LA分子丢失，而所研究的其他金属则产生相反的效果（多结合1 - 2个LA分子）。在大多数情况下，观察到的效果与金属诱导的HSA四级结构变化无关。然而，锌诱导的HSA结合LA能力下降可能是由于多聚体HSA形式的积累。与钙/镁结合相反，锌或铜与HSA结合会导致其疏水表面发生明显变化。总体而言，二价金属离子在不同程度上调节HSA的LA结合能力和亲和力。LA与钙结合到HSA上相互协同支持。锌和铜会在HSA的疏水表面、四级结构及其LA结合能力方面引起更明显的变化。AD中这些离子的代谢失衡可能会改变HSA与LA、其他脂肪酸以及与AD相关的疏水性物质之间的相互作用。
