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Related Concept Videos

Molecular Chaperones and Protein Folding03:00

Molecular Chaperones and Protein Folding

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The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
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Regulation of the Unfolded Protein Response01:31

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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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Amyloid Fibrils03:03

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Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
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Export of Misfolded Proteins out of the ER01:32

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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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Mitochondrial Precursor Proteins01:39

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Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70  chaperones are targetted to TOM20-TOM22 receptor complexes.
Most of the mitochondrial...
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Protein Folding Quality Check in the RER01:29

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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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Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Proteostasis, crucial for neuronal function, is challenged by the unique demands of neuronal projections.
  • Maintaining protein folding and preventing aggregation is vital in neurons due to their complex structure and synaptic activity.

Purpose of the Study:

  • To investigate how neurons maintain proteostasis in their projections under stress.
  • To identify the mechanisms of chaperone mRNA localization and translation in neuronal dendrites.

Main Methods:

  • High-resolution fluorescence microscopy was used to visualize mRNA localization in mouse and human neurons.
  • Proteotoxic stress was induced to observe changes in chaperone mRNA transport and translation.
  • Depletion or expression of specific RNA-binding proteins (FUS, hnRNPA2/B1) was used to assess their role in mRNA localization.

Main Results:

  • Chaperone mRNAs, particularly heat shock protein 70 family member A8 (HSPA8), are localized to neuronal dendrites via microtubule transport.
  • Proteotoxic stress enhances the asymmetric localization and translation efficiency of HSPA8 mRNA in dendrites.
  • Impaired dendritic localization of HSPA8 mRNA was observed when key RNA-binding proteins (FUS, hnRNPA2/B1) were manipulated.

Conclusions:

  • Neurons employ a stress-responsive mechanism involving RNA-binding proteins to enhance dendritic localization of HSPA8 mRNA.
  • This targeted mRNA transport and translation is critical for maintaining proteostasis in neuronal projections.
  • The findings suggest a novel pathway for preventing neurodegeneration by bolstering neuronal defense against proteotoxic stress.