His18 promotes reactive oxidative stress production in copper-ion mediated human islet amyloid polypeptide aggregation.
His18 promotes reactive oxidative stress production in copper-ion mediated human islet amyloid polypeptide aggregation.
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His18 促进铜离子介导的人胰岛淀粉样多肽聚集中反应性氧化应激的产生
作者：
铜离子在人类胰岛淀粉样多肽（hIAPP）聚集中起关键作用，其在超过90%的2型糖尿病（T2 D）患者中被发现。Cu（II）在hIAPP的细胞毒性中的作用已经在两个方面进行了探索：抑制纤维状结构的形成和刺激活性氧（ROS）的产生。在这项工作中，我们进行了光谱研究Cu（II）与几个hIAPP片段及其变体以及相互作用。电子顺磁共振（EPR）测量和Amplex Red分析表明，与Cu（ii）共孵育的hIAPP（11-28）溶液中产生的H2 O2的量显著高于hIAPP（1-11）和hIAPP（28-37）。此外，当hIAPP（11-28）的His 18被Arg（R）或Ser（S）取代时，H2 O2水平严重降低，表明His 18是Cu（ii）与hIAPP（11-28）结合以促进H2 O2产生的关键残基。这可能是因为从肽到Cu（ii）离子的电子捐赠将导致氧化还原活性络合物的形成，其可以刺激H2 O2的形成。总体而言，这项研究提供了进一步深入了解Cu（II）诱导的活性氧生成的分子机制。
Copper ions play a critical role in human islet amyloid polypeptide (hIAPP) aggregation, which has been found in more than 90% of patients with type-2 diabetes (T2D). The role of Cu(ii) in the cell cytotoxicity with hIAPP has been explored in two aspects: inhibiting the formation of fibrillar structures and stimulating the generation of reactive oxygen species (ROS). In this work, we carried out spectroscopic studies of Cu(ii) interacting with several hIAPP fragments and their variants as well. Electron paramagnetic resonance (EPR) measurements and Amplex Red analysis showed that the amount of H2O2 generated in hIAPP(11-28) solution co-incubated with Cu(ii) was remarkably more than hIAPP(1-11) and hIAPP(28-37). Furthermore, the H2O2 level was seriously reduced when His18 of hIAPP(11-28) was replaced by Arg(R) or Ser(S), indicating that His18 is the key residue of Cu(ii) binding to hIAPP(11-28) to promote H2O2 generation. This is likely because the donation of electrons from the peptide to Cu(ii) ions would result in the formation of the redox-active complexes, which could stimulate the formation of H2O2. Overall, this study provides further insight into the molecular mechanism of Cu(ii) induced ROS generation.
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影响因子：
3.6
作者：
Jeong HR;An SS
通讯作者：
An SS
DOI：
10.1039/c3cp44542a
发表时间：
2013-08-14
期刊：
Physical chemistry chemical physics : PCCP
影响因子：
--
作者：
Lee EC;Ha E;Singh S;Legesse L;Ahmad S;Karnaukhova E;Donaldson RP;Jeremic AM
通讯作者：
Jeremic AM
影响因子：
46.2
作者：
DeToma AS;Salamekh S;Ramamoorthy A;Lim MH
通讯作者：
Lim MH
影响因子：
8.4
作者：
Lee SJC;Choi TS;Lee JW;Lee HJ;Mun DG;Akashi S;Lee SW;Lim MH;Kim HI
通讯作者：
Kim HI
影响因子：
11.4
作者：
Cheignon C;Tomas M;Bonnefont-Rousselot D;Faller P;Hureau C;Collin F
通讯作者：
Collin F