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HSP70-binding motifs function as protein quality control degrons.

Amanda B Abildgaard1, Vasileios Voutsinos1, Søren D Petersen2

  • 1Department of Biology, The Linderstrøm-Lang Centre for Protein Science, University of Copenhagen, Copenhagen, Denmark.

Cellular and Molecular Life Sciences : CMLS
|January 7, 2023
PubMed
Summary

Chaperone-binding sites can act as protein quality control (PQC) degrons, targeting misfolded proteins for degradation. This suggests overlapping sequences for chaperone binding and PQC-linked protein degradation.

Keywords:
ChaperoneProteasomeProtein degradationProtein quality controlProtein stabilityProtein unfolding

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Protein quality control (PQC) prevents cellular damage from misfolded proteins via proteasomal degradation.
  • PQC degrons share hydrophobic features with chaperone-binding regions, hinting at a functional link.

Purpose of the Study:

  • To investigate if chaperone-binding regions can function as PQC degrons.
  • To identify the molecular machinery involved in PQC degron function of chaperone-binding motifs.

Main Methods:

  • Tested the Hsp70-binding APPY motif as a degron in yeast and human cells.
  • Identified interacting proteins including Hsp70, Hsp110, Fes1, and E3 Ubr1 in yeast.
  • Screened sequence variations within the APPY motif for degron activity.
  • Correlated Hsp70-binding sites in the yeast proteome with protein abundance and half-life.

Main Results:

  • The canonical Hsp70-binding APPY motif functions as a dose-dependent PQC degron in both yeast and human cells.
  • A broad range of sequences within the APPY motif retain degron function.
  • Increased Hsp70-binding sites in yeast proteins correlate with lower protein abundance and shorter half-lives.

Conclusions:

  • Chaperone-binding sites can serve as PQC degrons, mediating proteasomal degradation of misfolded proteins.
  • The sequence characteristics enabling chaperone binding overlap with those mediating PQC-linked degradation.