title: Polyglutamine shows a urea-like affinity for unfolded cytosolic protein.
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.
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA. jengland@princeton.edu
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: England
authors.forename: Daniel
authors.initials: D
authors.lastname: Kaganovich
mesh_terms: D000818:Animals; D002460:Cell Line; D003600:Cytosol / Q000737:chemistry*; D006801:Humans; D006816:Huntington Disease; D018613:Microscopy, Confocal; D010455:Peptides / Q000494:pharmacology*; D011489:Protein Denaturation / Q000187:drug effects; D058767:Protein Unfolding / Q000187:drug effects*; D011506:Proteins / Q000187:drug effects; D013816:Thermodynamics; D014508:Urea
chemical_list: D010455:Peptides; D011506:Proteins; C097188:polyglutamine; D014508:Urea