Author: Yan, Pengrong; Patel, Hardik J; Sharma, Sahil; Corben, Adriana; Wang, Tai; Panchal, Palak; Yang, Chenghua; Sun, Weilin; Araujo, Thais L; Rodina, Anna; Joshi, Suhasini; Robzyk, Kenneth; Gandu, Srinivasa; White, Julie R; de Stanchina, Elisa; Modi, Shanu; Janjigian, Yelena Y; Hill, Elizabeth G; Liu, Bei; Erdjument-Bromage, Hediye; Neubert, Thomas A; Que, Nanette L S; Li, Zihai; Gewirth, Daniel T; Taldone, Tony; Chiosis, Gabriela
Title: Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone. Cord-id: ss9ygoxi Document date: 2020_6_30
ID: ss9ygoxi
Snippet: 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 permiss
Document: 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.
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