在Saccharomyces cerevisiae中内细胞网膜局部化膜蛋白折叠的机制和工程
Yuhuan Luo1, Jian-Jiang Zhong1, Han Xiao1
1State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dong-chuan Road, Shanghai, 200240, China.
Metabolic engineering
|March 10, 2025
概括
增强酵母体内质网膜 (ER) 膜蛋白折叠是合成生物学的关键. 本综述详细介绍了改善蛋白质折叠的策略,这对于代谢工程应用至关重要.
科学领域:
- 合成生物学 合成生物学
- 代谢工程是代谢工程.
- 生物化学 生化学
背景情况:
- 像细胞P450一样,内细胞网膜 (ER) 局部化的膜蛋白对合成生物学宿主至关重要.
- 由于复杂的细胞相互作用,许多异质膜蛋白在Saccharomyces cerevisiae的ER中无法正确折叠.
- 适当的折叠对于在工程生物体中赋予催化功能至关重要.
研究的目的:
- 审查ER中膜蛋白折叠的基本过程和影响因素.
- 总结目前的代谢工程策略,以增强酵母中正确的膜蛋白折叠.
- 确定局限性,并提出该领域未来的研究方向.
主要方法:
- 关于膜蛋白折叠机制和影响其因素的文献综述.
- 对Saccharomyces cerevisiae应用的各种代谢工程方法的分析.
- 讨论包括蛋白质工程,陪伴者共表达和脂质环境调制在内的策略.
主要成果:
- 膜蛋白折叠受氨基酸序列,协同翻译过程,分子陪伴者,ER质量控制和脂质环境的影响.
- 代谢工程策略提供了改善异质膜蛋白折叠的途径.
- 目前的方法面临着需要进一步调查的局限性.
结论:
- 在酵母中优化膜蛋白折叠对于推进代谢工程和合成生物学至关重要.
- 需要进一步的研究来克服现有的挑战,并开发更强大的折叠策略.
- 将蛋白质工程,系统生物学和脂管学结合在一起的跨学科方法将是必不可少的.
相关概念视频
01:29Protein Folding Quality Check in the RER
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ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
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01:32Export of Misfolded Proteins out of the ER
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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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01:34Directing Proteins to the Rough Endoplasmic Reticulum
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The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
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01:45Tail-anchoring of Proteins in the ER Membrane
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Tail-anchored, or TA, proteins are estimated to make up to 3-5% of membrane proteins found in the eukaryotic cell. Such proteins have a single transmembrane domain located approximately 30 amino acid residues upstream from the C-terminal end. As a result, the signal recognition particle (SRP) cannot guide a TA protein to the ER membrane for cotranslational insertion. Hence, they are integrated into the ER membrane post-translationally using their C-terminal end as the anchor. TA proteins...
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01:26Protein Modifications in the RER
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Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal...
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal...
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01:27Post-translational Translocation of Proteins to the RER
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A sizable fraction of proteins destined for ER are first synthesized in the cell cytosol and then transported across the ER membrane–a process called post-translational translocation. Similar to cotranslationally translocated proteins, these proteins also use the Sec translocon complex to enter the ER lumen.
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
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