HSP70-binding motifs function as protein quality control degrons

Amanda B. Abildgaard, Vasileios Voutsinos, Søren D. Petersen, Fia B. Larsen, Caroline Kampmeyer, Kristoffer E. Johansson, Amelie Stein, Tommer Ravid, Claes Andréasson, Michael K. Jensen, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen

Research output: Contribution to journalArticlepeer-review

Abstract

Protein quality control (PQC) degrons are short protein segments that target misfolded proteins for proteasomal degradation, and thus protect cells against the accumulation of potentially toxic non-native proteins. Studies have shown that PQC degrons are hydrophobic and rarely contain negatively charged residues, features which are shared with chaperone-binding regions. Here we explore the notion that chaperone-binding regions may function as PQC degrons. When directly tested, we found that a canonical Hsp70-binding motif (the APPY peptide) functioned as a dose-dependent PQC degron both in yeast and in human cells. In yeast, Hsp70, Hsp110, Fes1, and the E3 Ubr1 target the APPY degron. Screening revealed that the sequence space within the chaperone-binding region of APPY that is compatible with degron function is vast. We find that the number of exposed Hsp70-binding sites in the yeast proteome correlates with a reduced protein abundance and half-life. Our results suggest that when protein folding fails, chaperone-binding sites may operate as PQC degrons, and that the sequence properties leading to PQC-linked degradation therefore overlap with those of chaperone binding.

Original languageAmerican English
Article number32
JournalCellular and Molecular Life Sciences
Volume80
Issue number1
DOIs
StatePublished - 7 Jan 2023

Keywords

  • Chaperone
  • Proteasome
  • Protein degradation
  • Protein quality control
  • Protein stability
  • Protein unfolding

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Molecular Medicine
  • Molecular Biology
  • Cell Biology
  • Pharmacology

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