An oligomeric state-dependent switch in the ER enzyme FICD regulates AMPylation and deAMPylation of BiP
| Autor: | Randy J. Read, Luke A. Perera, Yahui Yan, Claudia Rato, David Ron, Lisa Neidhardt, Stephen H. McLaughlin, Steffen Preissler |
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| Přispěvatelé: | Perera, Luke A [0000-0002-0032-1176], Rato, Claudia [0000-0002-3971-046X], Yan, Yahui [0000-0001-6934-9874], Neidhardt, Lisa [0000-0003-0256-5040], McLaughlin, Stephen H [0000-0001-9135-6253], Read, Randy J [0000-0001-8273-0047], Preissler, Steffen [0000-0001-7936-9836], Ron, David [0000-0002-3014-5636], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
BiP
Protein Conformation Endoplasmic Reticulum Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Protein structure Structural Biology Transferase AMPylation Humans Molecular Biology Adenylylation deAMPylation Endoplasmic Reticulum Chaperone BiP Heat-Shock Proteins 030304 developmental biology FICD 0303 health sciences General Immunology and Microbiology biology General Neuroscience Endoplasmic reticulum HEK 293 cells Active site Membrane Proteins Articles Protein Biosynthesis & Quality Control Nucleotidyltransferases Cell biology HEK293 Cells Membrane protein Chaperone (protein) biology.protein Protein Multimerization Protein Processing Post-Translational 030217 neurology & neurosurgery |
| Zdroj: | The EMBO Journal |
| DOI: | 10.17863/cam.43330 |
| Popis: | AMPylation is an inactivating modification that alters the activity of the major endoplasmic reticulum (ER) chaperone BiP to match the burden of unfolded proteins. A single ER‐localised Fic protein, FICD (HYPE), catalyses both AMPylation and deAMPylation of BiP. However, the basis for the switch in FICD's activity is unknown. We report on the transition of FICD from a dimeric enzyme, that deAMPylates BiP, to a monomer with potent AMPylation activity. Mutations in the dimer interface, or of residues along an inhibitory pathway linking the dimer interface to the enzyme's active site, favour BiP AMPylation in vitro and in cells. Mechanistically, monomerisation relieves a repressive effect allosterically propagated from the dimer interface to the inhibitory Glu234, thereby permitting AMPylation‐competent binding of MgATP. Moreover, a reciprocal signal, propagated from the nucleotide‐binding site, provides a mechanism for coupling the oligomeric state and enzymatic activity of FICD to the energy status of the ER. |
| Databáze: | OpenAIRE |
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