title: ADP ribosylation adapts an ER chaperone response to short-term fluctuations in unfolded protein load.
abstract: Gene expression programs that regulate the abundance of the chaperone BiP adapt the endoplasmic reticulum (ER) to unfolded protein load. However, such programs are slow compared with physiological fluctuations in secreted protein synthesis. While searching for mechanisms that fill this temporal gap in coping with ER stress, we found elevated levels of adenosine diphosphate (ADP)-ribosylated BiP in the inactive pancreas of fasted mice and a rapid decline in this modification in the active fed state. ADP ribosylation mapped to Arg470 and Arg492 in the substrate-binding domain of hamster BiP. Mutations that mimic the negative charge of ADP-ribose destabilized substrate binding and interfered with interdomain allosteric coupling, marking ADP ribosylation as a rapid posttranslational mechanism for reversible inactivation of BiP. A kinetic model showed that buffering fluctuations in unfolded protein load with a recruitable pool of inactive chaperone is an efficient strategy to minimize both aggregation and costly degradation of unfolded proteins.
authors.affiliation: Metabolic Research Laboratories, University of Cambridge, Cambridge CB2 0QQ, England, UK. jec202@cam.ac.uk
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Chambers
authors.forename: Kseniya
authors.initials: K
authors.lastname: Petrova
authors.forename: Giulia
authors.initials: G
authors.lastname: Tomba
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.forename: David
authors.initials: D
authors.lastname: Ron
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry*; D000495:Allosteric Site; D000818:Animals; D016880:Anisotropy; D020134:Catalytic Domain; D002460:Cell Line; D006224:Cricetinae; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D051379:Mice; D018832:Molecular Chaperones; D009154:Mutation; D011489:Protein Denaturation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D012266:Ribose / Q000737:chemistry
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011506:Proteins; D000244:Adenosine Diphosphate; D012266:Ribose