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Related Concept Videos

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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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Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
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Protein glycosylation starts in the ER lumen and continues in the Golgi apparatus. Glycosyltransferases catalyze the addition of sugar molecules or glycosylation of proteins. Usually, these enzymes add sugars to the hydroxyl groups of selected serine or threonine residues to form O-linked glycans or the amino groups of asparagine residues to form N-linked glycans. Different positions on the same polypeptide chain can contain differently linked glycans.
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Glycosylation, the most common post-translational modification for proteins, serves diverse functions. Adding sugars to proteins makes the proteins more resistant to proteolytic digestion. Glycosylated proteins can act as markers and receptors to promote cell-cell adhesion. Additionally, they have many essential quality control functions in the cell, such as correct protein folding and facilitating transport of misfolded proteins to the cytosol, which can be degraded.
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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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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...
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Regulated N-glycosylation controls chaperone function and receptor trafficking.

Mengxiao Ma1, Ramin Dubey1, Annie Jen2

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This study reveals a new endoplasmic reticulum (ER) pathway regulating N-glycosylation. This pathway involves HSP90B1 and CCDC134, controlling protein folding and preventing degradation, impacting cell signaling and development.

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • N-glycosylation is a crucial post-translational modification occurring in the endoplasmic reticulum (ER).
  • It is catalyzed by oligosaccharyltransferases (OSTs), with OST-A and OST-B being key enzymes in humans.
  • N-glycosylation was traditionally viewed as a general housekeeping process.

Purpose of the Study:

  • To investigate novel regulatory mechanisms of N-glycosylation beyond its housekeeping role.
  • To identify factors that modulate the activity of oligosaccharyltransferase A (OST-A).
  • To understand the functional implications of regulated N-glycosylation in cellular processes and development.

Main Methods:

  • Genetic analyses to identify interacting partners of OST-A.
  • Investigating the role of ER chaperones and luminal proteins in N-glycosylation.
  • Studying the impact of pathway disruption on WNT and IGF1R signaling pathways.
  • Analyzing effects on bone development and the disorder osteogenesis imperfecta.

Main Results:

  • A novel ER pathway was identified that modulates OST-A activity.
  • Genetic studies linked OST-A to HSP90B1 and CCDC134.
  • HSP90B1's N-terminal peptide templates a translocon complex with CCDC134 and OST-A, protecting HSP90B1 during folding.
  • This complex prevents HSP90B1 hyperglycosylation and degradation.
  • Disruption of this pathway leads to impaired WNT and IGF1R signaling.
  • Pathway disruption is linked to osteogenesis imperfecta, a bone developmental disorder.

Conclusions:

  • N-glycosylation is not solely a housekeeping function but is actively regulated in the ER.
  • Specificity factors, such as CCDC134 and HSP90B1, play a role in controlling N-glycosylation.
  • Regulated N-glycosylation is essential for proper cell surface receptor signaling.
  • This regulation is critical for normal tissue development, as demonstrated by its role in bone formation.