Total chemical synthesis of LC3A and LC3B activity-based probes

Huppelschoten, Y.; Buchardt, J.; Nielsen, T.E.; Sapmaz, A.; Noort, G.V. van (2023)

Article / Letter to editor

Autophagy is a conserved cellular process involved in the degradation of intercellular materials. During this process, double-membrane vesicles called autophagosomes engulf cytoplasmic components ready for degradation. A key component in the formation of autophagosomes are the autophagy-related (Atg) proteins, including microtubule-associated protein light chain 3A (LC3A) and 3B (LC3B). After the C-terminus of LC3 is conjugated to a phospholipid, it promotes the elongation of the phagosome and provides a docking station for the delivery of proteins ready for degradation. Since dysregulation of the autophagy pathway has been associated with a variety of human diseases, components of this process have been considered as potential therapeutic targets. However, the mechanistic details of LC3-specific ligases and deconjugation enzymes are far from unraveled and chemical tools for activity profiling could aid in affording more insights into this process. Herein, we describe a native chemical ligation approach for the synthesis of two LC3 activity-based probes (ABPs). Initial studies show that the probes covalently interact with the cysteine protease ATG4B, showcasing the potential of these probes to unravel mechanistic and structural details.

• activity-based probe
• chemical synthesis
• protein chemistry

• All authors: Huppelschoten, Y.; Buchardt, J.; Nielsen, T.E.; Sapmaz, A.; Noort, G.V. van
• Date: 2023-03-01
• Journal: Biomedicines
• Volume: 11
• Issue: 3
• DOI: doi:10.3390/biomedicines11030884