Open Access
Chemical and biological approaches synergize to ameliorate protein-folding diseases
Mu T. Mu,Ong D.S.T. Ong,Wang Y. Wang +2 more
- Vol. 21, Iss: 10, pp 402-404
TLDR
It is demonstrated that the innate cellular protein homeostasis capacity can be enhanced to fold mutated enzymes that would otherwise misfold and be degraded, using small molecule proteostasis regulators.Abstract:
Loss-of-function diseases are often caused by a mutation in a protein traversing the secretory pathway that compromises the normal balance between protein folding, trafficking, and degradation. We demonstrate that the innate cellular protein homeostasis, or proteostasis, capacity can be enhanced to fold mutated enzymes that would otherwise misfold and be degraded, using small molecule proteostasis regulators. Two proteostasis regulators are reported that alter the composition of the proteostasis network in the endoplasmic reticulum through the unfolded protein response, increasing the mutant folded protein concentration that can engage the trafficking machinery, restoring function to two nonhomologous mutant enzymes associated with distinct lysosomal storage diseases. Coapplication of a pharmacologic chaperone and a proteostasis regulator exhibits synergy because of the former's ability to further increase the concentration of trafficking-competent mutant folded enzymes. It may be possible to ameliorate loss-of-function diseases by using proteostasis regulators alone or in combination with a pharmacologic chaperone.read more
Citations
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Journal ArticleDOI
Molecular chaperones in protein folding and proteostasis
TL;DR: It is suggested that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease, which may spring from a detailed understanding of the pathways underlying proteome maintenance.
Journal ArticleDOI
Molecular Chaperone Functions in Protein Folding and Proteostasis
TL;DR: This review focuses on recent advances in understanding the mechanisms of chaperone action in promoting and regulating protein folding and on the pathological consequences of protein misfolding and aggregation.
Journal ArticleDOI
Biological and Chemical Approaches to Diseases of Proteostasis Deficiency
TL;DR: It is proposed that small molecules can enhance proteostasis by binding to and stabilizing specific proteins (pharmacologic chaperones) or by increasing the protestasis network capacity (proteostasis regulators) and that such therapeutic strategies, including combination therapies, represent a new approach for treating a range of diverse human maladies.
Journal ArticleDOI
Comprehensive characterization of genes required for protein folding in the endoplasmic reticulum
Martin C. Jonikas,Sean R. Collins,Vladimir Denic,Eugene Oh,Erin M. Quan,Volker Schmid,Jimena Weibezahn,Blanche Schwappach,Peter Walter,Jonathan S. Weissman,Maya Schuldiner +10 more
TL;DR: This strategy revealed multiple conserved factors critical for endoplasmic reticulum folding, including an intimate dependence on the later secretory pathway, a previously uncharacterized six-protein transmembrane complex, and a co-chaperone complex that delivers tail-anchored proteins to their membrane insertion machinery.
Journal ArticleDOI
Protein Folding and Modification in the Mammalian Endoplasmic Reticulum
Ineke Braakman,Neil J. Bulleid +1 more
TL;DR: Analysis of the human genome reveals that approximately a third of all open reading frames code for proteins that enter the endoplasmic reticulum (ER), demonstrating the importance of this organelle for global protein maturation.
References
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Signal integration in the endoplasmic reticulum unfolded protein response
David Ron,Peter Walter +1 more
TL;DR: Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids.
Journal ArticleDOI
The mammalian unfolded protein response
TL;DR: In the endoplasmic reticulum (ER), secretory and transmembrane proteins fold into their native conformation and undergo posttranslational modifications important for their activity and structure as mentioned in this paper.
Journal ArticleDOI
Molecular chaperones in protein folding and proteostasis
TL;DR: It is suggested that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease, which may spring from a detailed understanding of the pathways underlying proteome maintenance.
Journal ArticleDOI
A Model for Random Sampling and Estimation of Relative Protein Abundance in Shotgun Proteomics
TL;DR: A linear dynamic range over 2 orders of magnitude is demonstrated by using the number of spectra (spectral sampling) acquired for each protein by the data-dependent acquisition of peptides eluting into the mass spectrometer.
Journal ArticleDOI
Global Survey of Phosphotyrosine Signaling Identifies Oncogenic Kinases in Lung Cancer
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TL;DR: By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.