ArticleJournal of the American Chemical Society2015
Conformational Stability and Pathogenic Misfolding of the Integral Membrane Protein PMP22.
Article in Journal of the American Chemical Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 69 citations in OpenAlex.
- Peripheral Myelin Protein-22 and Its Prominence in Charcot-Marie-Tooth Disease.Chemical reviews · 2026Review
- The Shape of Things to Come: α-Helical Membrane Protein Folding on the Ribosome.Chemical reviews · 2026Review
- High-throughput screening identifies a trafficking corrector for long QT syndrome-associated KCNQ1 variants.JCI insight · 2026Article
- Charcot-Marie-Tooth disease type 1E: clinical natural history and molecular impact of PMP22 variants.Brain : a journal of neurology · 2026Article
- High Throughput Screening Identifies a Small Molecule Trafficking Corrector for Long-QT Syndrome Associated KCNQ1 Variants.bioRxiv : the preprint server for biology · 2025Article
- The lipid bilayer strengthens the cooperative network of membrane proteins.Science advances · 2025Article
- Unifying perspectives on the activity and genotypic targeting of pharmacological chaperones.The Journal of biological chemistry · 2025Review
- Charcot-Marie-Tooth disease type 1E: Clinical Natural History and Molecular Impact ofmedRxiv : the preprint server for health sciences · 2025Article
- Small-Molecule Modulators of Lipid Raft Stability and Protein-Raft Partitioning.bioRxiv : the preprint server for biology · 2024Article
- Cystic Fibrosis Modulator Therapies: Bridging Insights from CF to other Membrane Protein Misfolding Diseases.Israel journal of chemistry · 2024Article
- Disrupting the transmembrane domain interface between PMP22 and MPZ causes peripheral neuropathy.iScience · 2024Article
- One-shot design elevates functional expression levels of a voltage-gated potassium channel.Protein science : a publication of the Protein Society · 2024Article
- Infrared Photoactivation Enables Improved Native Top-Down Mass Spectrometry of Transmembrane Proteins.Analytical chemistry · 2023Article
- Implantable Electroceutical Approach Improves Myelination by Restoring Membrane Integrity in a Mouse Model of Peripheral Demyelinating Neuropathy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Altered Expression ofInternational journal of molecular sciences · 2022Article
- Towards generalizable predictions for G protein-coupled receptor variant expression.Biophysical journal · 2022Article
- Untangling the complexity of membrane protein folding.Current opinion in structural biology · 2022Review
- Lipid bilayer induces contraction of the denatured state ensemble of a helical-bundle membrane protein.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Evolutionary coupling analysis guides identification of mistrafficking-sensitive variants in cardiac KFrontiers in pharmacology · 2022Article
- Compendium of causative genes and their encoded proteins for common monogenic disorders.Protein science : a publication of the Protein Society · 2022Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Despite broad biochemical relevance, our understanding of the physiochemical reactions that limit the assembly and cellular trafficking of integral membrane proteins remains superficial. In this work, we report the first experimental assessment of the relationship between the conformational stability of a eukaryotic membrane protein and the degree to which it is retained by cellular quality control in the secretory pathway. We quantitatively assessed both the conformational equilibrium and cellular trafficking of 12 variants of the α-helical membrane protein peripheral myelin protein 22 (PMP22), the intracellular misfolding of which is known to cause peripheral neuropathies associated with Charcot-Marie-Tooth disease (CMT). We show that the extent to which these mutations influence the energetics of Zn(II)-mediated PMP22 folding is proportional to the observed reduction in cellular trafficking efficiency. Strikingly, quantitative analyses also reveal that the reduction of motor nerve conduction velocities in affected patients is proportional to the extent of the mutagenic destabilization. This finding provides compelling evidence that the effects of these mutations on the energetics of PMP22 folding lie at the heart of the molecular basis of CMT. These findings highlight conformational stability as a key factor governing membrane protein biogenesis and suggest novel therapeutic strategies for CMT.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.