Human γS-Crystallin-Copper Binding Helps Buffer against Aggregation Caused by Oxidative Damage.,Biochemistry

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Human γS-Crystallin-Copper Binding Helps Buffer against Aggregation Caused by Oxidative Damage.
Biochemistry ( IF 2.9 ) Pub Date : 2020-06-08 , DOI: 10.1021/acs.biochem.0c00293
Kyle W Roskamp ₁ , Sana Azim ₂ , Günther Kassier ₂ , Brenna Norton-Baker _{1,

2} , Marc A Sprague-Piercy ₃ , R J Dwyane Miller _{2,

4} , Rachel W Martin _{1,

3}

Affiliation

Divalent metal cations can play a role in protein aggregation diseases, including cataract. Here we compare the aggregation of human γS-crystallin, a key structural protein of the eye lens, via mutagenesis, ultraviolet light damage, and the addition of metal ions. All three aggregation pathways result in globular, amorphous-looking structures that do not elongate into fibers. We also investigate the molecular mechanism underlying copper(II)-induced aggregation. This work was motivated by the observation that zinc(II)-induced aggregation of γS-crystallin is driven by intermolecular bridging of solvent-accessible cysteine residues, while in contrast, copper(II)-induced aggregation of this protein is exacerbated by the removal of solvent-accessible cysteines via mutation. Here we find that copper(II)-induced aggregation results from a complex mechanism involving multiple interactions with the protein. The initial protein–metal interactions result in the reduction of Cu(II) to Cu(I) with concomitant oxidation of γS-crystallin. In addition to the intermolecular disulfides that represent a starting point for aggregation, intramolecular disulfides also occur in the cysteine loop, a region of the N-terminal domain that was previously found to mediate the early stages of cataract formation. This previously unobserved ability of γS-crystallin to transfer disulfides intramolecularly suggests that it may serve as an oxidation sink for the lens after glutathione levels have become depleted during aging. γS-Crystallin thus serves as the last line of defense against oxidation in the eye lens, a result that underscores the chemical functionality of this protein, which is generally considered to play a purely structural role.

中文翻译：

人γS-结晶蛋白-铜的结合有助于缓冲液抗氧化损伤引起的聚集。

二价金属阳离子可在蛋白质聚集疾病（包括白内障）中起作用。在这里，我们通过诱变，紫外线损伤和添加金属离子，比较了人眼晶状体的关键结构蛋白-γS-晶状蛋白的聚集。所有这三种聚集途径均导致球形，无定形的结构不会伸长为纤维。我们还研究了铜（II）诱导聚集的分子机制。这项工作的动机是观察到锌（II）诱导的γS-晶状蛋白的聚集是由溶剂可及的半胱氨酸残基的分子间桥接驱动的，而相反，铜（II）诱导的该蛋白质的聚集因去除而加剧突变获得溶剂可及的半胱氨酸。在这里，我们发现铜（II）诱导的聚集是由涉及与蛋白质的多次相互作用的复杂机制导致的。最初的蛋白质-金属相互作用导致γS-晶状体蛋白伴随氧化而将Cu（II）还原为Cu（I）。除了代表聚集起点的分子间二硫化物外，分子内二硫化物也存在于半胱氨酸环中，该半胱氨酸环是先前发现的介导白内障形成早期阶段的N末端结构域区域。以前无法观察到的γS-晶状蛋白分子内转移二硫键的能力表明，在老化过程中谷胱甘肽水平耗尽后，它可能充当晶状体的氧化沉。因此，γS-晶状体蛋白可以作为防止晶状体氧化的最后一道防线，

更新日期：2020-06-30

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