Oligomerization of Cu,Zn-Superoxide Dismutase (SOD1) by Docosahexaenoic Acid and Its Hydroperoxides In Vitro: Aggregation Dependence on Fatty Acid Unsaturation and Thiols.
Oligomerization of Cu,Zn-Superoxide Dismutase (SOD1) by Docosahexaenoic Acid and Its Hydroperoxides In Vitro: Aggregation Dependence on Fatty Acid Unsaturation and Thiols.
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DOI：
10.1371/journal.pone.0125146
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Miyamoto S
中科院分区：
文献类型：
--
作者：
Appolinário PP;Medinas DB;Chaves-Filho AB;Genaro-Mattos TC;Cussiol JR;Netto LE;Augusto O;Miyamoto S
二十二碳六烯酸（C22：6，n-3，DHA）是一种多不饱和脂肪酸，在大脑中高度富集。这种脂肪酸很容易被氧化，产生氢过氧化物作为主要产物。铜锌超氧化物歧化酶（SOD 1）聚集是肌萎缩侧索硬化症（ALS）的常见标志，其形成背后的分子机制尚未完全了解。在这里，我们研究了DHA及其氢过氧化物（DHAOOH）对体外人SOD 1寡聚化的影响。DHA诱导高分子量（HMW）SOD 1物质（>700 kDa）的形成。聚集依赖于游离巯基，主要发生在其载脂蛋白形式的蛋白质。SOD 1与DHA的孵育伴随着蛋白质结构的变化，导致蛋白质疏水斑块的暴露和非淀粉样蛋白聚集体的形成。定点突变研究表明，野生型中的Cys 6和Cys 111以及ALS连接的G93 A突变体中的Cys 6是聚集所需的。相反，DHAOOH不诱导HMW物质形成，但促进对SDS和硫醇还原剂具有抗性的apo-SOD 1的异常共价二聚化。总的来说，我们的数据表明，DHA和DHAOOH诱导不同类型的apo-SOD 1寡聚化，分别导致HMW和低分子量物质的形成。
Docosahexaenoic acid (C22:6, n-3, DHA) is a polyunsaturated fatty acid highly enriched in the brain. This fatty acid can be easily oxidized yielding hydroperoxides as primary products. Cu, Zn-Superoxide dismutase (SOD1) aggregation is a common hallmark of Amyotrophic Lateral Sclerosis (ALS) and the molecular mechanisms behind their formation are not completely understood. Here we investigated the effect of DHA and its hydroperoxides (DHAOOH) on human SOD1 oligomerization in vitro. DHA induced the formation of high-molecular-weight (HMW) SOD1 species (>700 kDa). Aggregation was dependent on free thiols and occurred primarily with the protein in its apo-form. SOD1 incubation with DHA was accompanied by changes in protein structure leading to exposure of protein hydrophobic patches and formation of non-amyloid aggregates. Site-directed mutagenesis studies demonstrated that Cys 6 and Cys 111 in wild-type and Cys 6 in ALS-linked G93A mutant are required for aggregation. In contrast, DHAOOH did not induce HMW species formation but promoted abnormal covalent dimerization of apo-SOD1 that was resistant to SDS and thiol reductants. Overall, our data demonstrate that DHA and DHAOOH induce distinct types of apo-SOD1 oligomerization leading to the formation of HMW and low-molecular-weight species, respectively.
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影响因子：
14.5
作者：
Jonsson, PA;Graffmo, KS;Marklund, SL
通讯作者：
Marklund, SL
DOI：
10.1073/pnas.0704307104
发表时间：
2007-07-03
影响因子：
11.1
作者：
Banci, Lucia;Bertini, Ivano;Whitelegge, Julian P.
通讯作者：
Whitelegge, Julian P.
影响因子：
12.7
作者：
Kerman, Aaron;Liu, Hsueh-Ning;Chakrabartty, Avijit
通讯作者：
Chakrabartty, Avijit
DOI：
10.1016/j.bbrc.2005.01.164
发表时间：
2005-04-15
影响因子：
3.1
作者：
Fu, XM;Zhang, XF;Chang, ZY
通讯作者：
Chang, ZY
影响因子：
4.8
作者：
Hwang, Young-Mi;Stathopulos, Peter B.;Meiering, Elizabeth M.
通讯作者：
Meiering, Elizabeth M.