铜（Cu）作为人体的必需微量金属元素，对调控生命过程至关重要。铜作为细胞内关键蛋白酶的辅助因子，广泛参与了细胞内诸多生理生化过程，如线粒体氧化呼吸链、过氧化物清除、铜结合蛋白的生物合成、生物的休息-活动周期等。铜代谢的紊乱往往与铜死亡、DNA损伤、肿瘤免疫逃避、门克斯氏（Menkes）综合症、威尔逊氏（Wilson）病、神经退行性疾病等密切相关。

铜转运网络是铜生物学功能的基础，而铜结合蛋白是铜转运网络的重要组成成分，因此深入理解铜的生物学功能需要完整绘制铜转运网络，发现和验证更多含铜蛋白的功能和调控机制。然而，含铜蛋白的发现和鉴定目前仍然缺乏足够的方法，特别是如何通过蛋白质组学进行大规模含铜蛋白的发现具有极大的挑战性。近年来邻近标记技术逐渐成为研究生物大分子相互作用蛋白组的有力工具。APEX2邻近标记技术能以较高的时空分辨率来识别直接、弱或瞬时相互作用的蛋白质，已被广泛应用于细胞内复杂的蛋白质相互作用网络研究。但是，APEX2邻近标记技术中使用的过氧化氢（H₂O₂）可能影响细胞内对氧化敏感的蛋白质组的鉴定。TurboID邻近标记技术利用了无毒性的生物素作为底物，能够在不影响细胞生理状态的情况下实现邻近标记，目前已经越来越多的应用于蛋白质组学的研究。

本论文以铜伴侣蛋白抗氧化蛋白1（ATOX1）为诱饵，将ATOX1与邻近标记技术相融合的策略，通过有效捕获ATOX1邻近蛋白质，并绘制其相互作用网络，从中发现新的铜结合蛋白。我们首先对比了基于APEX2和TurboID的邻近标记蛋白质组，发现二者具有特定的氨基酸偏好性和结构域偏好性。为了提高准确性，我们将APEX2和TurboID这两种邻近标记技术捕获的共有蛋白质组作为高置信度的ATOX1邻近蛋白质网络，并通过GO分析和KEGG通路分析验证了ATOX1参与的已知生理功能和作用通路，说明两种邻近标记技术的综合运用能够准确地绘制ATOX1邻近蛋白质网络，为发现新的铜结合蛋白提供可靠的数据支撑。从ATOX1邻近蛋白质网络中，本研究发现和验证了一个之前未报道的全新铜结合蛋白硫氧还蛋白还原酶1（TrxR1）。体外实验结果表明铜可以结合在TrxR1的催化活性中心，从而抑制了TrxR1通过其C端氧化还原中心还原Trx1的过程，导致Trx1氧化态的增加。然而，铜的结合不会影响NADPH还原TrxR1的N端氧化还原中心的过程，也不会导致TrxR1的蛋白质二级结构、二聚化状态或热稳定性发生改变。硝基化作为调控蛋白质活性、定位、稳定性和相互作用的重要翻译后修饰，广泛参与到细胞的生理过程当中，而Trx1是调节蛋白质去硝基化的关键蛋白酶之一。本研究发现铜会进一步导致Trx1失去去硝基化的功能，最终引起细胞内蛋白质的S-亚硝基化（SNO）修饰水平的升高。

综上所述，本研究通过邻近标记蛋白质组学技术有效地绘制了全细胞铜伴侣蛋白ATOX1相互作用的邻近蛋白质网络，为发现新的铜结合蛋白提供了重要数据库资源，并拓展了对细胞内铜的生物学功能的认知。

Copper (Cu), as an essential trace metal in the body, is crucial for life. Copper serves as an indispensable protein cofactor and widely participates in various physiological and biochemical processes within the cell. These processes include mitochondrial oxidative phosphorylation, removal of peroxides, biosynthesis of copper-binding proteins, and the biological rest-activity cycle. Disruptions of copper metabolism are often closely associated with cuproptosis, DNA damage, tumor immune evasion, Menkes disease, Wilson's disease, and neurodegenerative diseases.

The copper transport network decides cellular copper biology, and copper-binding proteins are vital components of this network. Therefore, the mapping of copper trafficking networks and the discovery of copper-binding proteins is essential for a deeper understanding of copper biology. Identifying copper-binding proteins lacks an efficiently and accurately tool to confirm copper binding and its binding sites. Especially, large-scale discovery of copper-binding proteins at the proteome level is significant challenging. In recent years, proximity labeling techniques have gradually become powerful tools for studying the interactions between large biomolecules. The APEX2 proximity labeling technique can identify direct, weak, or transient protein interactions with high spatiotemporal resolution and has been widely applied in the study of complex protein interaction networks within cells. However, the use of hydrogen peroxide in the APEX2 proximity labeling technique may affect oxidation-sensitive proteins and pathways within the cell. On the other hand, the TurboID proximity labeling technique utilizes non-toxic biotin as a substrate, allowing for proximity labeling without affecting the physiological state of the cell, which has been widely applied for proteome research.

Here, this study integrates the copper chaperone protein antioxidant 1 (ATOX1) with proximity labeling techniques to capture the ATOX1-proximal protein network, aiming to discover new copper-binding proteins. We first compared the proximity-labeled proteomes based on APEX2 and TurboID, revealing their respective amino acid and domain preferences. To enhance the accuracy of the proximity-labeled proteome, the study further analyzed the overlap in the APEX2 and TurboID proteomes, regarded as the ATOX1-specific proximal network with high confidence. GO and KEGG analyses demonstrated that this network effectively recapitulated the known physiological functions and pathways related to ATOX1, confirming that the combination of both proximity labeling techniques can accurately depict the ATOX1-specific proximal protein network, providing crucial resource for the discovery of copper-binding proteins. From the network, we identified a novel copper-binding protein, thioredoxin reductase 1 (TrxR1). The results revealed that copper can bind to the catalytic center of TrxR1, inhibiting the reduction of Trx1 by TrxR1 through its C-terminal redox center and leading to an increase in the oxidized state of Trx1. However, copper binding does not affect the process of NADPH reducing the N-terminal redox center of TrxR1. or induce changes in the secondary structure, dimerization state, or thermal stability of TrxR1. Nitrosylation, a type of post-translation modification, regulates protein signaling, activities, and interactions. Given that Trx1 possesses denitrosylation activity, the results showed that copper decreased the denitrosylation activity of Trx1, ultimately leading to an elevation in the S-nitrosylation (SNO) modification level of intracellular proteins.

This research demonstrates that proximity labeling techniques can effectively depict the ATOX1-specific proximal protein network, serving as an important resource for discovering new copper-binding proteins. Additionally, the study expands our understanding on the cellular copper biology.

第一章 引言 1
1.1 生命中的铜 4
1.1.1 人体中铜的摄入与分布 4
1.1.2 小肠上皮细胞对铜的吸收 5
1.1.3 细胞内铜的转运 6
1.1.4 铜在细胞内的功能 8
1.1.5 铜紊乱相关的人体疾病 10
1.2 铜蛋白的发现方法 13
1.2.1 生物信息学在预测金属结合蛋白质中的应用 14
1.2.2 基于共进化的机器学习预测蛋白质中的金属结合蛋白 15
1.2.3 基于金属结合结构域预测蛋白质组中的金属蛋白 16
1.2.4 利用固定化金属离子亲和层析技术发现铜结合蛋白 18
1.2.5 利用酵母双杂交法发现铜结合蛋白质 19
1.3 邻近标记技术 21
1.3.1 基于APEX2的邻近标记技术 23
1.3.2 基于BioID的邻近标记技术 25
1.3.3 基于TurboID的邻近标记技术 26
1.4 本章小结与本研究课题 27
1.4.1 前期工作基础 28
1.4.2 本研究的立题依据 29
1.4.3 本研究的科学意义 29
第二章 材料与方法 31
2.1 实验材料 31
2.1.1 细胞系 31
2.1.2 实验材料 31
2.1.3 实验仪器 35
2.2 实验方法 36
2.2.1 细胞系的培养与保存 36
2.2.2 真核细胞表达质粒的构建 38
2.2.3 原核细胞表达质粒的构建 39
2.2.4 真核细胞的转染 41
2.2.5 聚丙烯酰胺凝胶电泳（SDS-PAGE） 42
2.2.6 蛋白质免疫印迹（Western blot） 42
2.2.7 电感耦合等离子体质谱（ICP-MS） 42
2.2.8 基于APEX2的邻近标记 43
2.2.9 基于TurboID的邻近标记 44
2.2.10 二甲基标记 45
2.2.11 蛋白质质谱鉴定与数据分析 45
2.2.12 蛋白质的原核系统表达与纯化 46
2.2.13 配体-金属电子转移（LMCT）吸收带的监测 47
2.2.14 微量热泳动（MST）实验 47
2.2.15 近紫外圆二色谱（Near-UV CD） 48
2.2.16 远紫外圆二色谱（Far-UV CD） 48
2.2.17 蛋白质结合铜的解离常数的测定 48
2.2.18 蛋白质与[Cu(BCA)2]3-的竞争实验 50
2.2.19 基于邻近标记的亲和下拉实验 50
2.2.20 免疫荧光共定位实验 51
2.2.21 蛋白质免疫共沉淀（co-IP）实验 51
2.2.22 表面等离子体共振（SPR）实验 52
2.2.23 铜传递的尺寸排阻色谱法（SEC）实验 53
2.2.24 原核表达与纯化的TrxR1酶活性的测定 53
2.2.25 真核细胞内TrxR酶活性的测定 54
2.2.26 实时荧光定量PCR（RT-qPCR） 54
2.2.27 非还原聚丙烯酰胺凝胶电泳（Non-reduced SDS-PAGE） 55
2.2.28 TrxR1辅因子含量的测定 55
2.2.29 差示扫描量热法分析（DSF）蛋白质稳定性 56
2.2.30 蛋白质热位移（Thermol shift）分析 56
2.2.31 停留光谱实验 56
2.2.32 Trx1氧化水平的表征 57
2.2.33 细胞内S-亚硝基化（SNO）修饰蛋白质的检测 58
2.2.34 基于CRISPR/Cas9的基因敲入（Knock-in） 59
2.2.35 基因敲入的纯合子细胞系的筛选与鉴定 59
2.2.36 基于基因敲入APEX2的邻近标记 60
第三章 基于邻近标记技术绘制ATOX1邻近蛋白质网络 61
3.1 本章引言与研究思路 61
3.1.1 铜伴侣蛋白ATOX1的结构特征 61
3.1.2 铜伴侣蛋白ATOX1的分子生物学功能 62
3.1.3 铜伴侣蛋白ATOX1的病理生理学功能 63
3.1.4 本章研究思路 64
3.2 实验结果与讨论 65
3.2.1 基于APEX2的邻近标记 65
3.2.2 基于TurboID的邻近标记 69
3.2.3 基于APEX2与TurboID的ATOX1邻近蛋白质组的比较 73
3.2.4 ATOX1邻近蛋白质网络的绘制 77
3.3 本章小结 79
第四章 硫氧还蛋白还原酶1（TrxR1）的发现与鉴定 81
4.1 本章引言与研究思路 81
4.2 实验结果与讨论 83
4.2.1硫氧还蛋白还原酶1（TrxR1）的发现 83
4.2.2 TrxR1结合铜离子的鉴定 86
4.2.3 TrxR1与铜离子的解离常数的测定 88
4.2.4 TrxR1的铜结合位点的确定 89
4.2.5 TrxR1与ATOX1的相互作用 90
4.2.6 TrxR1与ATOX1之间的铜传递 93
4.3 本章小结 95
第五章 铜对TrxR1/Trx1系统的调控 97
5.1 本章引言与研究思路 97
5.2 实验结果与讨论 100
5.2.1 铜抑制TrxR1UC的酶活性 100
5.2.2 铜抑制细胞内TrxR1的酶活性 103
5.2.3 铜对TrxR1蛋白质结构及其稳定性的影响 106
5.2.4 铜对TrxR1催化反应过程的影响 109
5.2.5 铜调控TrxR1/Trx1的功能 112
5.3 本章小结 116
第六章 基于基因敲入（Knock-in）技术的策略优化 118
6.1 策略优化的思路 118
6.2 实验结果与讨论 119
6.2.1 基于CRISPR/Cas9的APEX2敲入 119
6.2.2 基因敲入（Knock-in）细胞系的邻近标记 123
6.3 本章小结 128
第七章 结论及展望 129
参考文献 132
致谢 150
北京大学学位论文原创性声明和使用授权说明 152

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