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Updated: Jul 2, 2026

Assays for the Degradation of Misfolded Proteins in Cells
Published on: August 28, 2016
Navigating Misfolded Terrain: ER-Associated Degradation of Membrane Proteins
Devanshi Agarwal1, Kristina Solorio-Kirpichyan1, Eric M Jordahl1
1Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, California 92093, United States.
Abstract:
Integral membrane proteins face unique folding challenges in the endoplasmic reticulum (ER) due to their hydrophobic transmembrane domains and complex topologies. Membrane protein misfolding disrupts ER homeostasis, contributing to diseases such as neurodegeneration, metabolic disorders, cystic fibrosis, and cancers. ER-associated degradation (ERAD) is a protein quality control pathway that detects, ubiquitinates, and retrotranslocates terminally misfolded proteins for proteasomal degradation in the cytosol. Recognition of membrane substrates involves multiple determinants, including topological lesions, exposed hydrophobic patches, and sequence-specific degrons. Recent advances in cryo-EM, functional genomics, and biochemical reconstitution studies have revealed new insights into the mechanistic actions of ERAD. This review addresses the current understanding of ERAD machinery dedicated to targeting misfolded membrane proteins, highlights emerging mechanistic models, and discusses how ERAD drives pathology. Understanding these principles will inform strategies for targeted manipulation of ER membrane protein quality control in health and disease.
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