Caption: Catalytic centre in Atg3. In the absence of Atg12-Atg5, a catalytic Cys234 (magenta) is oriented away from Thr213 (orange) which is essential for Atg3 activity. When Atg3 interacts with Atg12-Atg5, Atg3 causes a conformational change, which reorients Cys234 toward Thr213 and mediates the formation of a Atg8-phosphatidylethanolamine.
“This study reveals the mechanism of the key reaction that drives membrane biogenesis during autophagy,” explain Yoshinori Ohsumi, Machiko Sakoh-Nakatogawa and colleagues at Tokyo Institute of Technology, Institute of Microbial Chemistry and Hokkaido University.Autophagy is a bulk degradation system essential for cell survival under starvation conditions, and also allows cells to control over the quality of cell components. It is known to be linked to neurodegenerative and hepatic diseases and the subject of intense research interest.
The researchers also identify a regulatory function for this stage in the mechanism, as it ensures the proteins activate specifically at autophagy-related membranes.Background
Previous studies have drawn similarities between some of these Atg proteins in the series of reactions they undergo and protein ubiquitination, the modification of a protein by another so-called ubiquitin protein. The name ubiquitin originates from the ubiquity of the protein as it is found in almost all organisms and directs proteins to degradation by the proteasome or to transport to different compartments and locations in the cell.
Based on the structural information, the researchers introduced Cys residue at some locations on Atg3 and examined an intramolecular disulphide bond formation between the introduced Cys residue and a catalytic Cys residue which indicates the proximity of these Cys residues. From the intramolecular disulphide bond formation with or without an interaction of Atg12-Atg5, the researchers identified that Atg12-Atg5 introduces a conformational change in the catalytic centre of Atg3. Effects of various mutations for an intramolecular disulphide bond formation in the Cys mutants of Atg3 allowed the researchers to identify the role of the mutated amino acid residues in the suppression of activity in the absence of Atg12-Atg5.Atg12-Atg5 activation of Atg3 regulatory mechanism.
Journal informationMachiko Sakoh-Nakatogawa, Kazuaki Matoba, Eri Asai, Hiromi Kirisako, Junko Ishii, Nobuo N Noda, Fuyuhiko Inagaki, Hitoshi Nakatogawa & Yoshinori Ohsumi Atg12–Atg5 conjugate enhances E2 activity of Atg3 by rearranging its catalytic site. Nature Structural and Molecular Biology 20, 433-439 (2013).
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14.12.2017 | Institute for Research in Biomedicine (IRB Barcelona)
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