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An oligomeric state‐dependent switch in the ER enzyme FICD regulates AMP ylation and de AMP ylation of BiP
Author(s) -
Perera Luke A,
Rato Claudia,
Yan Yahui,
Neidhardt Lisa,
McLaughlin Stephen H,
Read Randy J,
Preissler Steffen,
Ron David
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019102177
Subject(s) - adenylylation , enzyme , dimer , endoplasmic reticulum , nucleotide , biochemistry , biology , biophysics , microbiology and biotechnology , chemistry , biosynthesis , gene , organic chemistry
AMP ylation 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 AMP ylation and de AMP ylation 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 de AMP ylates BiP, to a monomer with potent AMP ylation 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 AMP ylation in vitro and in cells. Mechanistically, monomerisation relieves a repressive effect allosterically propagated from the dimer interface to the inhibitory Glu234, thereby permitting AMP ylation‐competent binding of Mg ATP . 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 .