| Structural highlights
Function
FICD_HUMAN Adenylyltransferase that mediates the addition of adenosine 5'-monophosphate (AMP) to specific residues of target proteins. Able to inactivate Rho GTPases in vitro by adding AMP to RhoA, Rac and Cdc42. It is however unclear whether it inactivates GTPases in vivo and physiological substrates probably remain to be identified.[1] [2]
Publication Abstract from PubMed
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.
An oligomeric state-dependent switch in the ER enzyme FICD regulates AMPylation and deAMPylation of BiP.,Perera LA, Rato C, Yan Y, Neidhardt L, McLaughlin SH, Read RJ, Preissler S, Ron D EMBO J. 2019 Sep 18:e102177. doi: 10.15252/embj.2019102177. PMID:31531998[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Worby CA, Mattoo S, Kruger RP, Corbeil LB, Koller A, Mendez JC, Zekarias B, Lazar C, Dixon JE. The fic domain: regulation of cell signaling by adenylylation. Mol Cell. 2009 Apr 10;34(1):93-103. doi: 10.1016/j.molcel.2009.03.008. PMID:19362538 doi:http://dx.doi.org/10.1016/j.molcel.2009.03.008
- ↑ Engel P, Goepfert A, Stanger FV, Harms A, Schmidt A, Schirmer T, Dehio C. Adenylylation control by intra- or intermolecular active-site obstruction in Fic proteins. Nature. 2012 Jan 22;482(7383):107-10. doi: 10.1038/nature10729. PMID:22266942 doi:10.1038/nature10729
- ↑ Perera LA, Rato C, Yan Y, Neidhardt L, McLaughlin SH, Read RJ, Preissler S, Ron D. An oligomeric state-dependent switch in the ER enzyme FICD regulates AMPylation and deAMPylation of BiP. EMBO J. 2019 Sep 18:e102177. doi: 10.15252/embj.2019102177. PMID:31531998 doi:http://dx.doi.org/10.15252/embj.2019102177
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