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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.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
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Spatiotemporal Control of Protein Activity through Optogenetic Allosteric Regulation
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Controlling PROTACs with Light.

Shreya Verma1, Debasish Manna1

  • 1Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal, 462066, MP, India.

Chemmedchem
|June 20, 2020
PubMed
Summary
This summary is machine-generated.

Photochemistry enables precise control over proteolysis targeting chimeras (PROTACs). Photocaged and photoswitchable PROTACs offer new spatiotemporal methods for targeted protein degradation using light.

Keywords:
UV lightazobenzenesirradiationphotocagesprotein degradation

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Area of Science:

  • Chemical Biology
  • Molecular Biology
  • Photochemistry

Background:

  • Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that hijack the ubiquitin-proteasome system for targeted protein degradation.
  • Controlling the spatiotemporal activation of PROTACs is crucial for precise biological manipulation.
  • Photochemistry offers a powerful tool for external control over molecular processes.

Purpose of the Study:

  • To explore the integration of photochemistry with PROTAC technology.
  • To introduce photocaged and photoswitchable PROTACs for spatiotemporal control of protein degradation.
  • To compare the activation mechanisms and reversibility of photocaged and photoswitchable PROTACs.

Main Methods:

  • Design and synthesis of photocaged PROTACs incorporating optolabile protecting groups.
  • Development of photoswitchable PROTACs utilizing photoisomerizable azobenzene linkages.
  • Irradiation with specific wavelengths of light to trigger or reverse PROTAC activity.

Main Results:

  • Photocaged PROTACs are activated upon light-induced cleavage of the protecting group, leading to irreversible protein degradation.
  • Photoswitchable PROTACs undergo reversible cis-trans isomerization upon light exposure, modulating their protein degradation activity.
  • Both systems demonstrate light-dependent control over PROTAC function, with photoswitchable variants offering reversible deactivation.

Conclusions:

  • The fusion of photochemistry with PROTACs provides novel strategies for spatiotemporal control over targeted protein degradation.
  • Photocaged PROTACs enable light-triggered activation, while photoswitchable PROTACs allow for reversible on/off switching of protein degradation.
  • These photo-controlled PROTACs represent advanced tools for chemical biology research and potential therapeutic applications.