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Understanding the Autophagy Pathway Print

Autophagy is a process in which a double-membrane structure called an ‘autophagosome’ engulfs portions of a cell's cytoplasm, including organelles. The contents of the autophagosome are then directed for degradation in the lysosome, an organelle that breaks down waste and debris in cells so the raw materials can be reused. Recent research at the ALS clarifies key aspects of enzyme activity in this process.

Autophagy is key to maintaining cellular equilibrium, or homeostasis; however, dysregulation of autophagy has been implicated in several diseases. Central to autophagy is a ubiquitin-like protein (Ubl) system called Atg8. In general, Ubls serve as molecular tags, altering the fate of their targets. In autophagy, Atg8 is activated by its E1 enzyme Atg7, then handed off to its E2 enzyme Atg3, and finally attached to a lipid moiety (phosphatidylethanolamine) within the expanding autophagosome.

In recently published research, crystal and solution (SAXS) structural analysis performed at ALS Beamlines 8.2.2 and 12.3.1 shed light on the mechanism by which the E1 enzyme for autophagy transfers the Ubl Atg8 to the E2 enzyme.

This research shows that Atg7 functions in a manner distinct from other related E1 enzymes, namely E1s for ubiquitin, SUMO and Nedd8. Atg7, a homodimer, catalyses the transfer of Atg8 to Atg3: Atg3 bound to one Atg7 monomer accepts Atg8 from the opposite Atg7 protomer in the dimer. In addition to expanding our mechanistic understanding of the Atg8 system, this study identified a unique mode of E1-E2 binding, where a loop from Atg3 binds a conserved groove on Atg7. This Atg3 loop-Atg7 protein interface may serve as a potential therapeutic target to regulate autophagy.

 

Atg8 is transferred from the catalytic cysteine (green circle) of one Atg7 protomer to the catalytic cysteine of Atg3 (green circle) bound to the opposite Atg7 protomer within the dimer, in trans.

 



Work performed on ALS Beamlines 8.2.2 and 12.3.1.

Citation: A.M. Taherbhoy et al. "Atg8 transfer from Atg7 to Atg3: a distinctive E1-E2 architecture and mechanism in the autophagy pathway," Molecular Cell 44(3): 451-461 (2011).

This work was featured on the cover of Molecular Cell: Autophagy Ubiquitin-Like Protein Transfer In Trans.