Optimization of Protein Folding for Improved Secretion of Human Serum Albumin Fusion Proteins in Saccharomyces cerevisiae,Journal of Agricultural and Food Chemistry

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Optimization of Protein Folding for Improved Secretion of Human Serum Albumin Fusion Proteins in Saccharomyces cerevisiae
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2023-11-15 , DOI: 10.1021/acs.jafc.3c05330
Yanling Li _{1,

2} , Chufan Xiao _{1,

2} , Yuyang Pan _{1,

2} , Ling Qin _{1,

2} , Lin Zheng _{1,

2} , Mouming Zhao _{1,

2} , Mingtao Huang _{1,

2}

Affiliation

The successful expression and secretion of recombinant proteins in cell factories significantly depend on the correct folding of nascent peptides, primarily achieved through disulfide bond formation. Thus, optimizing cellular protein folding is crucial, especially for proteins with complex spatial structures. In this study, protein disulfide isomerases (PDIs) from various species were introduced into Saccharomyces cerevisiae to facilitate proper disulfide bond formation and enhance recombinant protein secretion. The impacts of these PDIs on recombinant protein production and yeast growth metabolism were evaluated by substituting the endogenous PDI1. Heterologous PDIs cannot fully compensate the endogenous PDI. Furthermore, protein folding mediators, PDI and ER oxidoreductase 1 (Ero1), from different species were used to increase the production of complex human serum albumin (HSA) fusion proteins. The validated folding mediators were then introduced into unfolded protein response (UPR)-optimized strains, resulting in a 7.8-fold increase in amylase-HSA and an 18.2-fold increase in albiglutide compared with the control strain. These findings provide valuable insights for optimizing protein folding and expressing HSA-based drugs.

中文翻译：

优化蛋白质折叠以改善酿酒酵母中人血清白蛋白融合蛋白的分泌

重组蛋白在细胞工厂中的成功表达和分泌很大程度上取决于新生肽的正确折叠，这主要通过二硫键的形成来实现。因此，优化细胞蛋白质折叠至关重要，特别是对于具有复杂空间结构的蛋白质。在这项研究中，将来自不同物种的蛋白质二硫键异构酶（PDI）引入酿酒酵母中，以促进适当的二硫键形成并增强重组蛋白的分泌。通过替换内源PDI 1来评估这些PDI对重组蛋白生产和酵母生长代谢的影响。异源PDI不能完全补偿内源PDI。此外，来自不同物种的蛋白质折叠介质 PDI 和 ER 氧化还原酶 1 (Ero1) 被用来增加复杂人血清白蛋白 (HSA) 融合蛋白的产量。然后将经过验证的折叠介质引入未折叠蛋白反应 (UPR) 优化菌株中，与对照菌株相比，淀粉酶-HSA 增加了 7.8 倍，阿必鲁肽增加了 18.2 倍。这些发现为优化蛋白质折叠和表达基于 HSA 的药物提供了宝贵的见解。

更新日期：2023-11-15

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