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Regulated Protein Degradation02:58

Regulated Protein Degradation

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It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
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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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Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
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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...
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Using In Vitro Fluorescence Resonance Energy Transfer to Study the Dynamics Of Protein Complexes at a Millisecond Time Scale
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14-3-3 proteins regulate cullin 7-mediated Eag1 degradation.

Chang-Heng Hsieh1, Chia-Cheng Chou2, Ya-Ching Fang1,3

  • 1Institute of Anatomy and Cell Biology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.

Cell & Bioscience
|January 31, 2023
PubMed
Summary

Endogenous 14-3-3 proteins act as chaperones for the Eag1 potassium channel, stabilizing its levels and potentially offering therapeutic strategies for neurodevelopmental diseases caused by Eag1 mutations.

Keywords:
Lysosomal degradationPotassium channelProteasomal degradationProtein interactionProtein stabilityUbiquitin ligase

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Mutations in the Eag1 (KV10.1; KCNH1) potassium channel are linked to congenital neurodevelopmental diseases.
  • Disease-associated Eag1 mutants exhibit altered gating and protein stability.
  • The E3 ubiquitin ligase cullin 7 (Cul7) and 14-3-3 protein are Eag1 binding partners, with Cul7 mediating degradation and 14-3-3 affecting channel activity.

Purpose of the Study:

  • To investigate the role of 14-3-3 proteins in regulating Eag1 protein homeostasis.
  • To determine if 14-3-3 proteins influence Eag1 degradation pathways.
  • To explore the therapeutic potential of modulating 14-3-3 function in Eag1-related disorders.

Main Methods:

  • Utilized human cell lines and native rat neurons.
  • Employed the peptide inhibitor difopein and RNA interference to disrupt 14-3-3 function.
  • Assessed Eag1 protein levels, ubiquitination, and degradation.
  • Investigated protein-protein interactions between Eag1, 14-3-3, and Cul7.
  • Performed structural analysis of Eag1 domains involved in 14-3-3 regulation.

Main Results:

  • Disrupting 14-3-3 function increased Eag1 protein levels independently of transcription.
  • Inhibition of 14-3-3 reduced Eag1 ubiquitination and degradation at the ER and plasma membrane.
  • 14-3-3 inhibition decreased excitotoxicity-associated Eag1 degradation in neurons.
  • 14-3-3 modulation affected Cul7-mediated Eag1 degradation and Eag1-Cul7 interaction.
  • Suppression of 14-3-3 function reduced degradation of disease-associated Eag1 mutants.

Conclusions:

  • Endogenous 14-3-3 proteins play a chaperone-like role in maintaining Eag1 protein homeostasis.
  • Modulators of 14-3-3 offer therapeutic potential for correcting Eag1 protein deficits in disease.