Deamidation of the human eye lens protein γS-crystallin accelerates oxidative aging.
Deamidation of the human eye lens protein γS-crystallin accelerates oxidative aging.
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DOI：
10.1016/j.str.2022.03.002
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发表时间：
2022-05-05
期刊：
影响因子：
5.7
通讯作者：
Martin, Rachel W.
中科院分区：
文献类型：
--
作者：
Norton-Baker, Brenna;Mehrabi, Pedram;Kwok, Ashley O.;Roskamp, Kyle W.;Rocha, Megan A.;Sprague-Piercy, Marc A.;von Stetten, David;Miller, R. J. Dwayne;Martin, Rachel W.
白内障是蛋白质沉淀导致的眼睛透镜混浊，每年影响数百万人。透镜蛋白，即晶状体蛋白，在白内障晶状体中表现出广泛的翻译后修饰（PTM）。最常见的PTM，脱酰胺和氧化，促进晶体蛋白聚集;然而，目前尚不清楚这些PTM如何准确地促进晶体蛋白不溶解。在这里，我们报告了六个晶体结构的透镜蛋白，γ S-晶体蛋白（γS）：一个野生型和五个脱酰胺的γS变体，从三到九个脱酰胺位点，样品老化后。脱酰胺突变不会改变γS的总体折叠;然而，增加脱酰胺导致加速二硫键形成。添加脱酰胺位点逐渐使蛋白质结构不稳定，并且脱酰胺变体显示出增加的聚集倾向。这些结果表明脱酰胺变体可用作加速老化的模型;观察到的结构变化为透镜中γ S-晶状体蛋白的氧化还原活性提供了支持。为了模拟有害的翻译后修饰在眼透镜中的积累，Norton-Baker等人研究了一系列白内障相关的透镜蛋白γ S-晶状体蛋白变体，这些变体具有逐渐增加的脱酰胺位点。增加的二硫键和聚集表明表面电荷和增加的动力学影响脱酰胺晶状体蛋白的白内障形成。
Cataract, a clouding of the eye lens from protein precipitation, affects millions of people every year. The lens proteins, the crystallins, show extensive post-translational modifications (PTMs) in cataractous lenses. The most common PTMs, deamidation and oxidation, promote crystallin aggregation; however, it is not clear precisely how these PTMs contribute to crystallin insolubilization. Here, we report six crystal structures of the lens protein, γS-crystallin (γS): one of the wild-type and five of deamidated γS variants, from three to nine deamidation sites, after sample aging. The deamidation mutations do not change the overall fold of γS; however, increasing deamidation leads to accelerated disulfide bond formation. Addition of deamidated sites progressively destabilized protein structure and the deamidated variants display an increased propensity for aggregation. These results suggest the deamidated variants are useful as models for accelerated aging; the structural changes observed provide support for redox activity of γS-crystallin in the lens. To mimic the accumulation of deleterious post-translational modifications in the eye lens, Norton-Baker et al. investigate a series of cataract-related variants of the lens protein γS-crystallin with progressively more deamidation sites. Increased disulfide bonding and aggregation suggest that both surface charge and increased dynamics impact cataract formation by deamidated crystallins.
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DOI：
10.1007/978-1-62703-691-7_18
发表时间：
2014
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Dyer, Kevin N;Hammel, Michal;Rambo, Robert P;Tsutakawa, Susan E;Rodic, Ivan;Classen, Scott;Tainer, John A;Hura, Greg L
通讯作者：
Hura, Greg L
影响因子：
4.8
作者：
Flaugh, Shannon L.;Mills, Ishara A.;King, Jonathan
通讯作者：
King, Jonathan
影响因子：
4.4
作者：
Dasari S;Wilmarth PA;Reddy AP;Robertson LJ;Nagalla SR;David LL
通讯作者：
David LL
DOI：
10.1016/j.pbiomolbio.2014.02.004
发表时间：
2014-07
影响因子：
3.8
作者：
Lampi KJ;Wilmarth PA;Murray MR;David LL
通讯作者：
David LL
影响因子：
3.4
作者：
Brubaker, William D.;Freites, J. Alfredo;Martin, Rachel W.
通讯作者：
Martin, Rachel W.