Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone.
GRP94
aberrant N-glycosylation
aberrant protein-protein interaction
cellular stress
chaperome-mediated protein connectivity dysfunction
epichaperome
protein mis-assembly
stable protein assembly
stress-mediated molecular dysfunction
targeted protein degradation-based therapeutics
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
30 06 2020
30 06 2020
Historique:
received:
12
02
2020
revised:
04
05
2020
accepted:
09
06
2020
entrez:
2
7
2020
pubmed:
2
7
2020
medline:
29
4
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32610141
pii: S2211-1247(20)30821-4
doi: 10.1016/j.celrep.2020.107840
pmc: PMC7372946
mid: NIHMS1608492
pii:
doi:
Substances chimiques
HSP70 Heat-Shock Proteins
0
Membrane Proteins
0
Molecular Chaperones
0
Polysaccharides
0
glucose-regulated proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
107840Subventions
Organisme : NIAID NIH HHS
ID : R21 AI090501
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA155226
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA192937
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213290
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG032969
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI077283
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172546
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA220499
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG061869
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA186866
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests G.C., P.Y., H.J.P., W.S., C.Y., and T.T. are inventors on patents covering PU-WS13 and associated composition of matter. G.C. is a founder of Samus Therapeutics and a member of its board of directors.
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