Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS
Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS
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SOD1 通过其进化不稳定的同源伴侣 hCCS 进行分子识别和成熟
DOI：
10.1371/journal.pbio.3000141
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发表时间：
2019
期刊：
影响因子：
9.8
通讯作者：
S. Hasnain
中科院分区：
文献类型：
--
作者：
F. A. Sala;F. A. Sala;G. Wright;S. Antonyuk;R. Garratt;S. Hasnain
超氧化物歧化酶-1(SOD1)的成熟包括一系列翻译后修饰，将新生多肽转化为稳定和活性的酶。在这个途径中，连续的折叠、金属离子结合和二硫化物的获取步骤可以通过与SOD1(CCS)的铜伴侣直接相互作用来催化。这一过程赋予了酶的活性，并减少了对非规范的、易于聚集的状态的访问。本文从反应前体物、中间体和产物的晶体结构出发，阐述了人铜伴侣对SOD1(HCCS)催化SOD1活化的作用机理。HCCS对未成熟SOD1的分子识别是由几个界面相互作用驱动的，这些界面相互作用提供了一个可在其上折叠的延伸表面。诱导配合作用依赖于未成熟的SOD1二硫化物亚环的结构可塑性，这一特征导致了神经退行性疾病中的错误折叠和聚集。络合作用特别稳定SOD1二硫化物亚环，启动它和铜转移的活性部位，同时延缓二硫化物的形成和络合物解离。关键的是，HCCS界面中单个不稳定的氨基酸替换降低了HCCS同源二聚体的亲和力，创建了一个可与未成熟的SOD1相互作用的HCCS池。HCCS底物的特异性、溶剂和生物膜之间的分离以及相互作用的瞬变是这种替代的直接结果。通过这种方式，HCCS催化的SOD1成熟被精心处理，以最大限度地减少铜浪费，并减少潜在有毒SOD1物种的产生。
Superoxide dismutase-1 (SOD1) maturation comprises a string of posttranslational modifications which transform the nascent peptide into a stable and active enzyme. The successive folding, metal ion binding, and disulphide acquisition steps in this pathway can be catalysed through a direct interaction with the copper chaperone for SOD1 (CCS). This process confers enzymatic activity and reduces access to noncanonical, aggregation-prone states. Here, we present the functional mechanisms of human copper chaperone for SOD1 (hCCS)–catalysed SOD1 activation based on crystal structures of reaction precursors, intermediates, and products. Molecular recognition of immature SOD1 by hCCS is driven by several interface interactions, which provide an extended surface upon which SOD1 folds. Induced-fit complexation is reliant on the structural plasticity of the immature SOD1 disulphide sub-loop, a characteristic which contributes to misfolding and aggregation in neurodegenerative disease. Complexation specifically stabilises the SOD1 disulphide sub-loop, priming it and the active site for copper transfer, while delaying disulphide formation and complex dissociation. Critically, a single destabilising amino acid substitution within the hCCS interface reduces hCCS homodimer affinity, creating a pool of hCCS available to interact with immature SOD1. hCCS substrate specificity, segregation between solvent and biological membranes, and interaction transience are direct results of this substitution. In this way, hCCS-catalysed SOD1 maturation is finessed to minimise copper wastage and reduce production of potentially toxic SOD1 species.
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DOI：
10.1073/pnas.040461197
发表时间：
2000-03-14
影响因子：
11.1
作者：
Wong, PC;Waggoner, D;Gitlin, JD
通讯作者：
Gitlin, JD
影响因子：
56.9
作者：
Rae, TD;Schmidt, PJ;O'Halloran, TV
通讯作者：
O'Halloran, TV
影响因子：
2.9
作者：
Lamb, AL;Torres, AS;Rosenzweig, AC
通讯作者：
Rosenzweig, AC
影响因子：
56.9
作者：
Bruijn, LI;Houseweart, MK;Cleveland, DW
通讯作者：
Cleveland, DW
DOI：
10.1073/pnas.0305143101
发表时间：
2004-04-20
影响因子：
11.1
作者：
Hough, MA;Grossmann, JG;Hasnain, SS
通讯作者：
Hasnain, SS