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Updated: Jun 5, 2026

Assays for the Degradation of Misfolded Proteins in Cells
Published on: August 28, 2016
Polyglutamine shows a urea-like affinity for unfolded cytosolic protein
Jeremy L England1, Daniel Kaganovich
1Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA. jengland@princeton.edu
Abstract:
Noting that the glutamine (Q) amino acid side-chain bears a striking resemblance to urea, the chemical denaturant, we argue on biophysical grounds that polyQ chains should possess a potent denaturant activity. Using live-cell confocal microscopy, we demonstrate that the surface of a polyQ inclusion denatures cytosolic proteins by binding and trapping them in an immobilized ring. We also show the reverse effect: that elevated local concentrations of unfolded protein in the cytosol can drive the co-localization and accumulation of short polyQ tracts that normally do not aggregate. Such a urea-like mechanism explains many past observations about polyQ-driven disruption of proteostasis and neurodegeneration.
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