The researchers reveal molecular mechanism of autophagy initiation

The researchers reveal molecular mechanism of autophagy initiation -

Researchers have found that factors Atg13 links autophagy initiation to another using a conformation similar chain, promoting the combination of various elements of the machinery initiation of autophagy, initiating autophagosome formation by recruiting Atg9 vesicles and phosphorylation of various factors Atg.

to live, it is necessary to not only the creatures to synthesize essential elements, but also degrade harmful or unnecessary components. Autophagy, an intracellular degradation system conserved among eukaryotic yeast to man, contributes to cellular homeostasis by isolation and degradation of various unnecessary components in the cells. Since autophagy dysfunction is linked to serious diseases such as neurodegeneration and cancer, the artificial control of autophagy promises to facilitate the development of therapeutic and preventive treatment for these serious and diseases.

In budding yeast, the complex ATG1 including ATG1, Atg13, Atg17, Atg29 and Atg31, mediates the initiation of autophagy (Figure 1). When autophagy is induced deprivation, these five components come together to form a dimer of pentamers. However, the formation of pentameric dimer alone is not enough to autophagy induction: and dozens pentameric complexes need to meet in a supramolecular complex initiation autophagy machinery elements. However, the molecular mechanism has been elusive.

Figure 1. Training model of autophagy induction machines.

In terms of the rich in nutrients, ATG1, Atg13 and Atg17-29-31-exist in complex without interacting with each other. In autophagy induction in conditions such as famine, they form a pentameric complex, which includes further an initiation complex machinery of autophagy giant.

This mystery was addressed by Professor Emeritus Yoshinori Ohsumi and Dr. Hayashi Yamamoto at the Tokyo Institute of Technology, and Drs. Nobuo Fujioka N. Noda and Yuko at Institute of Microbial Chemistry, in collaboration with other researchers. The researchers focused on Atg13 and analyzed its structure and function in vitro. The data revealed that Atg13 has a chain conformation in solution as intrinsically disordered and Atg13 two separate binding regions for Atg17. Detailed analysis of the interaction between Atg13 Atg17 and by X-ray crystallography have discovered that Atg13 Atg17 connects two molecules to each other using two binding regions. Analysis of the size of the complex revealed that ATG1 ATG1 complexes are connected to each other by Atg13, which results in the formation of a large complex initiation autophagy (Figure 2). When point mutations that impair the formation of this giant complex were introduced to Atg13, association of autophagy induction machines was completely blocked. These data suggest that the supramolecular complex resulting from the binding of complex ATG1 to each other by Atg13 functions as the initiation autophagy mechanism in vivo.

Figure 2. Molecular Mechanism of complex supramolecular assembly initiaition autophagy-mediated Atg13.

Atg13 (red) connects ATG1 (blue) and two Atg17s (green) to the other, thus promoting the formation of the giant complex.

then the machine function of autophagy initiation was studied in budding yeast, indicating that ATG1 phosphorylation activity is significantly improved when it is incorporated into the initiation complex supramolecular autophagy. In addition, it was revealed that the initiation mechanism of autophagy effectively recruits Atg9 vesicles, which serve as sources for the formation of the membrane and autophagosome Atg9 phosphorylated. These data collectively suggest that the initiation mechanism of autophagy not only mediates the formation of the initial isolation membrane by recruiting Atg9 vesicles, but also promotes autophagosome formation via autophagy-phosphorylating factors including Atg9 (Figure 3).

Figure 3. Model initiation autophagosome formation.

the initiation mechanism of autophagy mediates the formation of the initial isolation membrane by recruiting Atg9 vesicles. At the same time, the machines that phosphorylates Atg factors Atg9, thus promoting autophagosome formation.

These results are an important step in our quest to understand the molecular mechanisms of autophagy induction and autophagosome formation. A better understanding of the mechanisms of the first stages of autophagy promises to allow the development of compounds that regulate autophagy specifically with interesting clinical implications for the treatment of a range of serious diseases.