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Protein folding and secretion: mechanistic insights advancing recombinant protein production in S. cerevisiae.

ABSTRACT: The emergence of genomic approaches coupled to recombinant DNA technologies have identified the quality control systems that regulate proteostasis - biological pathways that modulate protein biogenesis, maturation, trafficking, and degradation. The elucidation of these pathways has become of growing importance in therapeutics as loss of proteostasis has been suggested to lead to a number of human diseases including Alzheimer's, Parkinson's Disease and Type II Diabetes. We anticipate that the most successful strategies for protein expression and therapeutics development may involve integration of protein engineering strategies with host manipulation, to exploit the cell's native stress response pathways and trafficking mechanisms. This review will highlight recent findings and mechanistic detail correlated to quality control in the early secretory pathway of Saccharomyces cerevisiae.

SUBMITTER: Young CL

PROVIDER: S-EPMC4253588 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Protein folding and secretion: mechanistic insights advancing recombinant protein production in S. cerevisiae.

Young Carissa L CL Robinson Anne S AS

Current opinion in biotechnology 20140715

The emergence of genomic approaches coupled to recombinant DNA technologies have identified the quality control systems that regulate proteostasis - biological pathways that modulate protein biogenesis, maturation, trafficking, and degradation. The elucidation of these pathways has become of growing importance in therapeutics as loss of proteostasis has been suggested to lead to a number of human diseases including Alzheimer's, Parkinson's Disease and Type II Diabetes. We anticipate that the mos ...[more]

PMID: 25032908

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Project description:Protein folding is often considered the flux controlling process in protein synthesis and secretion. Here, two previously isolated Saccharomyces cerevisiae strains with increased α-amylase productivity were analyzed in chemostat cultures at different dilution rates using multi-omics data. Based on the analysis, we identified different routes of the protein folding pathway to improve protein production. In the first strain, the increased abundance of proteins working on the folding process, coordinated with upregulated glycogen metabolism and trehalose metabolism, helped increase α-amylase productivity 1.95-fold compared to the level in the original strain in chemostat culture at a dilution rate of 0.2/h. The second strain further strengthened the folding precision to improve protein production. More precise folding helps the cell improve protein production efficiency and reduce the expenditure of energy on the handling of misfolded proteins. As calculated using an enzyme-constrained genome-scale metabolic model, the second strain had an increased productivity of 2.36-fold with lower energy expenditure than that of the original under the same condition. Further study revealed that the regulation of N-glycans played an important role in the folding precision control and that overexpression of the glucosidase Cwh41p can significantly improve protein production, especially for the strains with improved folding capacity but lower folding precision. Our findings elucidated in detail the mechanisms in two strains having improved protein productivity and thereby provided novel insights for industrial recombinant protein production as well as demonstrating how multi-omics analysis can be used for identification of novel strain-engineering targets.IMPORTANCE Protein folding plays an important role in protein maturation and secretion. In recombinant protein production, many studies have focused on the folding pathway to improve productivity. Here, we identified two different routes for improving protein production by yeast. We found that improving folding precision is a better strategy. Dysfunction of this process is also associated with several aberrant protein-associated human diseases. Here, our findings about the role of glucosidase Cwh41p in the precision control system and the characterization of the strain with a more precise folding process could contribute to the development of novel therapeutic strategies.

Dataset Information

Protein folding and secretion: mechanistic insights advancing recombinant protein production in S. cerevisiae.

Publications

Protein folding and secretion: mechanistic insights advancing recombinant protein production in S. cerevisiae.

Similar Datasets

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