Cells possess a mechanism called autophagy that wraps unnecessary components in membranes, transports them into the interiors of lysosomes or vacuoles in the cytoplasm, and degrades them. This membrane structure transported into vacuoles is called an autophagic body (AB), and "Atg15" is known as an enzyme that degrades the membrane of the AB in yeast. However, why Atg15, which possesses strong lipid-degrading activity, does not degrade the vacuolar membrane outside the AB, and how it is activated in vacuoles, were not understood.
A research team led by Associate Professor Tomoko Horie (Kawamata) of the Institute of Integrated Research at the Institute of Science Tokyo elucidated this activation mechanism through research combining the protein structure prediction AI AlphaFold, molecular dynamics simulations, experiments using yeast cells, and enzyme activity assays. Atg15 is usually in a state where its active site, which is responsible for degrading lipids, is inactive. When the carboxyl terminus (C-terminus) of Atg15 is cleaved by a protease in the vacuole and the protein binds to a membrane, the active site begins to function. Even after cleavage of the C-terminus, multiple stages of "safety mechanisms," such as conformational changes in Atg15 and regulation of membrane binding, exist to control the location and timing of enzyme activation. It was found that sophisticated mechanisms exist to prevent the degradation of membranes other than those that should be degraded.
In the future, investigating how other enzymes safely destroy only unnecessary membranes is expected to further advance our understanding of autophagy and lipid metabolism. In addition, the study has attracted attention as an example demonstrating the effectiveness of integrating AI, simulations, and experiments.
(Article: Masanori Nakajo)
