The Alarmone Diadenosine Tetraphosphate as a Cosubstrate for Protein AMPylation. Issue 8 (16th January 2023)

• Record Type: Journal Article
• Authors: Frese, Matthias; Saumer, Philip; Yuan, Yizhi; Herzog, Doreen; Höpfner, Dorothea; Itzen, Aymelt; Marx, Andreas
• Is Part Of: Angewandte Chemie international edition. Volume 62:Issue 8(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-16
• Subjects: AMPylation -- Activity-Based Protein Profiling -- Chemical Proteomics -- Nucleotides -- Post-Translational Modification; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202213279
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Diadenosine polyphosphates (Ap n As) are non‐canonical nucleotides whose cellular concentrations increase during stress and are therefore termed alarmones, signaling homeostatic imbalance. Their cellular role is poorly understood. In this work, we assessed Ap n As for their usage as cosubstrates for protein AMPylation, a post‐translational modification in which adenosine monophosphate (AMP) is transferred to proteins. In humans, AMPylation mediated by the AMPylator FICD with ATP as a cosubstrate is a response to ER stress. Herein, we demonstrate that Ap4 A is proficiently consumed for AMPylation by FICD. By chemical proteomics using a new chemical probe, we identified new potential AMPylation targets. Interestingly, we found that AMPylation targets of FICD may differ depending on the nucleotide cosubstrate. These results may suggest that signaling at elevated Ap4 A levels during cellular stress differs from when Ap4 A is present at low concentrations, allowing response to extracellular cues. Abstract : Ap4 A was investigated for its potential applicability as a cosubstrate in AMPylation mediated by FICD, instead of the common cosubstrate ATP. Proficient AMPylation capability of Ap4 A was observed, and new potential target proteins were found by chemical proteomics. Interestingly, AMPylation targets of FICD may differ depending on the cosubstrate.