AI Article Synopsis
- The unfolded protein response in the endoplasmic reticulum (ER) helps maintain protein folding by adjusting chaperone levels, like the major chaperone BiP, to manage unfolded proteins.
- Researchers found that an enzyme called FICD can both add and remove AMP from BiP, affecting its activity, as it AMPylates (inactivates) BiP when there's an excess of unfolded proteins.
- A specific amino acid (E234) in FICD plays a crucial role in switching its function between AMPylation and de-AMPylation, depending on the load of unfolded proteins in the ER.
Article Abstract
Protein folding homeostasis in the endoplasmic reticulum (ER) is defended by an unfolded protein response that matches ER chaperone capacity to the burden of unfolded proteins. As levels of unfolded proteins decline, a metazoan-specific FIC-domain-containing ER-localized enzyme (FICD) rapidly inactivates the major ER chaperone BiP by AMPylating T518. Here we show that the single catalytic domain of FICD can also release the attached AMP, restoring functionality to BiP. Consistent with a role for endogenous FICD in de-AMPylating BiP, FICD hamster cells are hypersensitive to introduction of a constitutively AMPylating, de-AMPylation-defective mutant FICD. These opposing activities hinge on a regulatory residue, E234, whose default state renders FICD a constitutive de-AMPylase in vitro. The location of E234 on a conserved regulatory helix and the mutually antagonistic activities of FICD in vivo, suggest a mechanism whereby fluctuating unfolded protein load actively switches FICD from a de-AMPylase to an AMPylase.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221731 | PMC |
| http://dx.doi.org/10.1038/nsmb.3337 | DOI Listing |
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