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首页> 外文期刊>Biochemistry >Concurrent Increases and Decreases in Local Stability and Conformational Heterogeneity in Cu, Zn Superoxide Dismutase Variants Revealed by Temperature-Dependence of Amide Chemical Shifts
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Concurrent Increases and Decreases in Local Stability and Conformational Heterogeneity in Cu, Zn Superoxide Dismutase Variants Revealed by Temperature-Dependence of Amide Chemical Shifts

机译：酰胺化学位移的温度依赖性揭示了Cu、Zn超氧化物歧化酶变体的局部稳定性和构象异质性同时增加和减少

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摘要

The chemical shifts of backbone amide protons in proteins are sensitive reporters of local structural stability and conformational heterogeneity, which can be determined from their readily measured linear and nonlinear temperature-dependences, respectively. Here we report analyses of amide proton temperature-dependences for native dimeric Cu, Zn superoxide dismutase (holo pWT SOD1) and structurally diverse mutant SOD1s associated with amyotrophic lateral sclerosis (ALS). Holo pWT SOD1 loses structure with temperature first at its periphery and, while having extremely high global stability, nevertheless exhibits extensive conformational heterogeneity, with similar to 1 in 5 residues showing evidence for population of low energy alternative states. The holo G93A and E100G ALS mutants have moderately decreased global stability, whereas V148I is slightly stabilized. Comparison of the holo mutants as well as the marginally stable immature monomeric unmetalated and disulfide-reduced (apo(2SH)) pWT with holo pWT shows that changes in the local structural stability of individual amides vary greatly, with average changes corresponding to differences in global protein stability measured by differential scanning calorimetry. Mutants also exhibit altered conformational heterogeneity compared to pWT. Strikingly, substantial increases as well as decreases in local stability and conformational heterogeneity occur, in particular upon maturation and for G93A. Thus, the temperature-dependence of amide shifts for SOD1 variants is a rich source of information on the location and extent of perturbation of structure upon covalent changes and ligand binding. The implications for potential mechanisms of toxic misfolding of SOD1 in disease and for general aspects of protein energetics, including entropy enthalpy compensation, are discussed.
机译：蛋白质中主链酰胺质子的化学位移是局部结构稳定性和构象异质性的敏感报告基因，这可以从它们易于测量的线性和非线性温度依赖性中分别确定。在这里，我们报告了与肌萎缩侧索硬化症 （ALS） 相关的天然二聚体 Cu、Zn 超氧化物歧化酶 （holo pWT SOD1） 和结构多样化的突变 SOD1 的酰胺质子温度依赖性分析。Holo pWT SOD1 首先在其外围失去温度的结构，虽然具有极高的全局稳定性，但仍然表现出广泛的构象异质性，与五分之一的残基相似，显示出低能量替代态种群的证据。全息 G93A 和 E100G ALS 突变体的全局稳定性适度降低，而 V148I 略微稳定。将全息突变体以及边缘稳定的未成熟单体非金属化和二硫键还原 （apo（2SH）） pWT 与全息 pWT 进行比较表明，单个酰胺的局部结构稳定性变化差异很大，平均变化对应于通过差示扫描量热法测量的全局蛋白质稳定性的差异。与 pWT 相比，突变体还表现出改变的构象异质性。引人注目的是，局部稳定性和构象异质性显着增加和减少，特别是在成熟时和 G93A 中。因此，SOD1 变体的酰胺位移的温度依赖性是关于共价变化和配体结合时结构扰动的位置和程度的丰富信息来源。讨论了对疾病中SOD1毒性错误折叠的潜在机制以及蛋白质能量学的一般方面（包括熵焓补偿）的影响。

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