Molecular stressors engender protein connectivity dysfunction through aberrant N-glycosylation of a chaperone Journal Article
| Authors: | Yan, P.; Patel, H. J.; Sharma, S.; Corben, A.; Wang, T.; Panchal, P.; Yang, C.; Sun, W.; Araujo, T. L.; Rodina, A.; Joshi, S.; Robzyk, K.; Gandu, S.; White, J. R.; de Stanchina, E.; Modi, S.; Janjigian, Y. Y.; Hill, E. G.; Liu, B.; Erdjument-Bromage, H.; Neubert, T. A.; Que, N. L. S.; Li, Z.; Gewirth, D. T.; Taldone, T.; Chiosis, G. |
| Article Title: | Molecular stressors engender protein connectivity dysfunction through aberrant N-glycosylation of a chaperone |
| Abstract: | Stresses associated with disease may pathologically remodel the proteome by both increasing interaction strength and altering interaction partners, resulting in proteome-wide connectivity dysfunctions. Chaperones play an important role in these alterations, but how these changes are executed remains largely unknown. Our study unveils a specific N-glycosylation pattern used by a chaperone, Glucose-regulated protein 94 (GRP94), to alter its conformational fitness and stabilize a state most permissive for stable interactions with proteins at the plasma membrane. This “protein assembly mutation’ remodels protein networks and properties of the cell. We show in cells, human specimens, and mouse xenografts that proteome connectivity is restorable by inhibition of the N-glycosylated GRP94 variant. In summary, we provide biochemical evidence for stressor-induced chaperone-mediated protein mis-assemblies and demonstrate how these alterations are actionable in disease. © 2020 The Authors Yan et al. show how N-glycosylation transforms a chaperone from a folding to a scaffolding protein that remodels protein connectivity, with the end result of proteome-wide dysfunction. This specific modification, exploited by cancer cells for enhanced fitness, is an actionable target in disease. © 2020 The Authors |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; drug targeting; antineoplastic agent; protein conformation; proteome; animal cell; mouse; animal tissue; complex formation; breast cancer; protein targeting; animal experiment; animal model; protein stability; antineoplastic activity; proteomics; drug mechanism; carcinogenicity; tumor cell; glycosylation; drug clearance; toxicity testing; esophagus cancer; biochemistry; protein synthesis inhibition; chemical modification; chaperone; cellular stress; grp94; glucose regulated protein 94; human; female; priority journal; article; epichaperome; aberrant n-glycosylation; aberrant protein-protein interaction; chaperome-mediated protein connectivity dysfunction; protein mis-assembly; stable protein assembly; stress-mediated molecular dysfunction; targeted protein degradation-based therapeutics; pu ws 13 |
| Journal Title: | Cell Reports |
| Volume: | 31 |
| Issue: | 13 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2020-06-30 |
| Start Page: | 107840 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2020.107840 |
| PUBMED: | 32610141 |
| PROVIDER: | scopus |
| PMCID: | PMC7372946 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 August 2020 -- Source: Scopus |
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