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Structure of ScAtg3 with truncations in N-terminal and flexible region (FR)
Structural highlights
FunctionATG3_YEAST E2 conjugating enzyme responsible for the E2-like covalent binding of phosphatidylethanolamine to the C-terminal Gly of ATG8. This step is required for the membrane association of ATG8. The formation of the ATG8-phosphatidylethanolamine conjugate is essential for autophagy and for the cytoplasm to vacuole transport (Cvt).[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedAutophagy depends on the E2 enzyme, Atg3, functioning in a conserved E1-E2-E3 trienzyme cascade that catalyzes lipidation of Atg8-family ubiquitin-like proteins (UBLs). Molecular mechanisms underlying Atg8 lipidation remain poorly understood despite association of Atg3, the E1 Atg7, and the composite E3 Atg12-Atg5-Atg16 with pathologies including cancers, infections and neurodegeneration. Here, studying yeast enzymes, we report that an Atg3 element we term E123IR (E1, E2, and E3-interacting region) is an allosteric switch. NMR, biochemical, crystallographic and genetic data collectively indicate that in the absence of the enzymatic cascade, the Atg3(E123IR) makes intramolecular interactions restraining Atg3's catalytic loop, while E1 and E3 enzymes directly remove this brace to conformationally activate Atg3 and elicit Atg8 lipidation in vitro and in vivo. We propose that Atg3's E123IR protects the E2~UBL thioester bond from wayward reactivity toward errant nucleophiles, while Atg8 lipidation cascade enzymes induce E2 active site remodeling through an unprecedented mechanism to drive autophagy. A switch element in the autophagy E2 Atg3 mediates allosteric regulation across the lipidation cascade.,Zheng Y, Qiu Y, Grace CRR, Liu X, Klionsky DJ, Schulman BA Nat Commun. 2019 Aug 9;10(1):3600. doi: 10.1038/s41467-019-11435-y. PMID:31399562[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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