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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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The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
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A dimer-monomer switch controls CHIP-dependent substrate ubiquitylation and processing.

Vishnu Balaji1, Leonie Müller1, Robin Lorenz2

  • 1Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital of Cologne, 50931 Cologne, Germany.

Molecular Cell
|August 26, 2022
PubMed
Summary
This summary is machine-generated.

The E3 ubiquitin ligase CHIP switches between dimer and monomer forms to control protein degradation, impacting cellular stress responses and longevity. This dimer-monomer transition, regulated by autoubiquitylation and chaperone binding, offers a new model for E3 ligase substrate selectivity.

Keywords:
C. elegansCHIPDAF-2E3 ligaseagingchaperonesinsulin signalinglongevityproteostasisubiquitin

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Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • The ubiquitin/proteasome system relies on E3 ubiquitin ligases for substrate selectivity.
  • The E3 ligase CHIP (CHIP) degrades both chaperone-dependent and independent proteins.
  • Understanding CHIP's substrate selection mechanism is crucial for cellular regulation.

Purpose of the Study:

  • To elucidate the structure-function relationship of CHIP.
  • To investigate the physiological roles of CHIP in *Caenorhabditis elegans* and human cells.
  • To uncover the regulatory mechanisms governing CHIP's substrate selectivity and activity.

Main Methods:

  • Structure-function analysis of CHIP.
  • Physiological studies in *Caenorhabditis elegans* and human cell models.
  • Analysis of CHIP autoubiquitylation and chaperone binding interactions.

Main Results:

  • CHIP dimer formation is essential for resistance to proteotoxic stress and preventing protein aggregation.
  • CHIP monomer promotes the degradation of the insulin receptor, influencing longevity.
  • A feedback loop involving CHIP autoubiquitylation and chaperone binding regulates the dimer-monomer transition and CHIP activity.

Conclusions:

  • CHIP functions as a molecular switch, with dimer and monomer states mediating distinct cellular processes.
  • The dimer-monomer transition is a key regulatory mechanism for CHIP activity in response to cellular stress.
  • This switch mechanism may represent a general principle for regulating substrate selectivity and ubiquitylation by combining different E3 ligases.