7b7z
DeAMPylation complex of monomeric FICD and AMPylated BiP (state 1)DeAMPylation complex of monomeric FICD and AMPylated BiP (state 1)
Structural highlights
FunctionFICD_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 PubMedThe endoplasmic reticulum (ER) Hsp70 chaperone BiP is regulated by AMPylation, a reversible inactivating post-translational modification. Both BiP AMPylation and deAMPylation are catalysed by a single ER-localised enzyme, FICD. Here we present crystallographic and solution structures of a deAMPylation Michaelis complex formed between mammalian AMPylated BiP and FICD. The latter, via its tetratricopeptide repeat domain, binds a surface that is specific to ATP-state Hsp70 chaperones, explaining the exquisite selectivity of FICD for BiP's ATP-bound conformation both when AMPylating and deAMPylating Thr518. The eukaryotic deAMPylation mechanism thus revealed, rationalises the role of the conserved Fic domain Glu234 as a gatekeeper residue that both inhibits AMPylation and facilitates hydrolytic deAMPylation catalysed by dimeric FICD. These findings point to a monomerisation-induced increase in Glu234 flexibility as the basis of an oligomeric state-dependent switch between FICD's antagonistic activities, despite a similar mode of engagement of its two substrates - unmodified and AMPylated BiP. Structures of a deAMPylation complex rationalise the switch between antagonistic catalytic activities of FICD.,Perera LA, Preissler S, Zaccai NR, Prevost S, Devos JM, Haertlein M, Ron D Nat Commun. 2021 Aug 18;12(1):5004. doi: 10.1038/s41467-021-25076-7. PMID:34408154[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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