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An oligomeric state‐dependent switch in the ER enzyme FICD regulates AMP ylation and de AMP ylation of BiP

DOI: 10.15252/embj.2019102177 DOI Help

Authors: Luke A. Perera (Cambridge Institute for Medical Research, University of Cambridge) , Claudia Rato (Cambridge Institute for Medical Research, University of Cambridge) , Yahui Yan (Cambridge Institute for Medical Research, University of Cambridge) , Lisa Neidhardt (Cambridge Institute for Medical Research, University of Cambridge) , Stephen H. Mclaughlin (MRC Laboratory of Molecular Biology) , Randy J. Read (Cambridge Institute for Medical Research, University of Cambridge) , Steffen Preissler (Cambridge Institute for Medical Research, University of Cambridge) , David Ron (Cambridge Institute for Medical Research, University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Embo Journal , VOL 66

State: Published (Approved)
Published: September 2019
Diamond Proposal Number(s): 15916

Open Access Open Access

Abstract: 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.

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 25/09/2019 09:22

Documents:
k5kj6hh6.pdf

Discipline Tags:

Catalysis Life Sciences & Biotech Biophysics Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)