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Disorder targets misorder in nuclear quality control degradation: a disordered ubiquitin ligase directly recognizes

Joel C Rosenbaum1, Eric K Fredrickson, Michelle L Oeser

  • 1Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.

Molecular Cell
|January 8, 2011
PubMed

Insights

The yeast protein San1 uses flexible, disordered domains to recognize and target various misfolded proteins for degradation. This mechanism allows the cell's protein quality control system to handle diverse abnormal protein shapes.

Area of Science:

  • Cellular biology
  • Biochemistry
  • Molecular genetics

Background:

  • Cellular proteostasis relies on protein quality control (PQC) systems to prevent toxic buildup of misfolded proteins.
  • PQC systems must identify diverse misfolded proteins while distinguishing them from functional proteins.

Purpose of the Study:

  • To investigate the mechanism by which the yeast nuclear PQC ubiquitin ligase San1 recognizes its misfolded substrates.
  • To elucidate how San1 distinguishes and targets a wide array of abnormally shaped proteins.

Main Methods:

  • Analysis of the structural and functional roles of San1's intrinsically disordered N- and C-terminal domains.
  • Identification of conserved sequence segments within disordered domains responsible for substrate recognition.

Main Results:

  • San1 directly recognizes misfolded substrates through its intrinsically disordered N- and C-terminal domains.
  • Specific, conserved segments within these disordered domains act as substrate-recognition sites.
  • These sites, embedded in flexible regions, confer plasticity to San1's substrate-binding capabilities.

Conclusions:

  • San1 utilizes intrinsically disordered domains with specific recognition sites to achieve broad substrate specificity.
  • This structural plasticity enables San1 to effectively target diverse misfolded proteins within the yeast nuclear PQC system.
  • The findings provide insight into the adaptability of PQC degradation machinery.

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