エンドプラズマ網膜におけるタンパク質の折りたたみに必要な遺伝子の包括的な特徴づけ
Martin C Jonikas1, Sean R Collins, Vladimir Denic
1Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA.
Science (New York, N.Y.)
|March 28, 2009
まとめ
研究者らは,エンドプラズマ網膜 (ER) 内でのタンパク質の折りたたみに関与する重要な酵母遺伝子を特定しました. この研究は,ER機能とタンパク質処理に不可欠な新しいタンパク質複合体を明らかにし,病気と老化に関する洞察を提供します.
科学分野:
- 細胞生物学 細胞生物学
- 分子生物学は分子生物学である.
- 遺伝学 遺伝学とは
背景:
- エンドプラズマ網膜 (ER) のタンパク質の誤折り合いは,老化と様々な病気に関連しています.
- 展開タンパク質応答 (UPR) は,ERの折り畳み状態を監視する細胞ストレス経路です.
研究 の 目的:
- UPRをセンサーとして使って,ERタンパク質の折りたたみに関与する遺伝子を識別する.
- 遺伝子の相互作用を通して,これらの遺伝子間の機能的関係を体系的にマッピングする.
主な方法:
- 酵母における展開タンパク質応答 (UPR) の定量レポーターを用いた包括的なスクリーン.
- 遺伝子の相互依存性を特徴付けるため,ダブルミュータントのUPRレベルを分析.
主要な成果:
- ERの折り畳みに欠かせない何百もの酵母遺伝子を特定しました.
- 後の分泌経路への強い依存性を発見した.
- 新しい6タンパク質のトランスメブラン複合体を発見した.
- コチャペロン複合体の特徴は,尾に固定されたタンパク質の挿入に関与している.
結論:
- この研究は,ERタンパク質の折り畳みに不可欠な保存された因子を明らかにしています.
- この系統的な遺伝分析アプローチは,複雑な細胞プロセスを解剖するために適用できます.
- 発見は,病気と老化におけるER機能不全を理解するための基盤を提供します.
関連する概念動画
01:29Protein Folding Quality Check in the RER
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...
01:32Export of Misfolded Proteins out of the ER
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...
01:31Regulation of the Unfolded Protein Response
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
01:37The Unfolded Protein Response
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
01:34Directing Proteins to the Rough Endoplasmic Reticulum
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...
01:26Protein Modifications in the RER
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 sequences.
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 sequences.