Prof. Hyun Kyu Song’s research team discovers a new function of protein complexes in the initial stage of autophagy, which helps maintain cell homeostasis

▲ Professor Hyun Kyu Song, Division of Life Sciences, College of Life Sciences and Biotechnology

Korean researchers are in the spotlight for discovering the fundamentals of how our body cells disassemble materials on their own to maintain homeostasis.

Professor Hyun Kyu Song, Division of Life Sciences, College of Life Sciences and Biotechnology and his team discovered that protein complexes interact with each other in the initial stage of autophagy, and successfully identified a new type of protein responsible for this interaction.

This research was supported by the Ministry of Science and ICT / National Research Foundation of Korea, and was published in the online version of the global journal Autophagy on August 7th.

•Title: The C-terminal region of ATG101 bridges ULK1 and PtdIns3K complex in autophagy initiation

•Authors: Prof. Hyun Kyu Song (corresponding author, Korea University), Byeong-Won Kim, Ph.D. (co-first author, Korea University), Yunjung Jin (co-first author, Korea University), Jiyea Kim (co-first author, National Cancer Center), Jun Hoe Kim (co-first author, Korea University), Juneyoung Jung (co- first author, Kyunghee University), Prof. Seongman Kang (Korea University), Prof. Ick Young Kim (Korea University), Prof. Joungmok Kim (Kyunghee University), Heesun Cheong, Ph.D. (National Cancer Center)

Autophagy is an essential mechanism for maintaining cell homeostasis by removing waste material inside cells and fighting off bacteria or viruses from the outside. It is closely related to degenerative cranial nerve disorders and even cancer. Among the three stages of autophagy, which can be categorized as initiation, elongation, and maturation, research on the elongation and maturation stages have been rather active, thanks to their simple signaling structure. However, the specific mechanisms of the initiation stage have not yet been discovered due to its complex protein and signaling structures.

The research team found that many proteins form different types of complexes (UheK1 complex or PI3K complex) in the initiation stage of autophagy, and that ATG101 plays an important role for transmitting signals among them. The team presented the 3D structure of the ATG101 protein, while discovering a new function of this protein.

The research team analyzed the structure of the ATG101-ATG13 complex by mass-producing the complex, splitting it, and conducting x-ray scattering and x-ray crystallography. Through this experiment, the team was able to identify the full structure of the undiscovered ATG101 protein and showed that signaling error is caused when damage occurs while this protein is binding with the PI3K complex, which is related to autophagy.

Professor Hyun Kyu Song explained, ”Through this research, we were able to present a high-resolution image of the unknown ATG101 protein’s full structure and discover new functions in how the ULK1 and PI3K complexes are connected.“ Professor Song added, ”The result of this study, which provides a better understanding of the complexes’ signaling structure in autophagy initiation, will help other studies concerned with autophagy such as degenerative cranial nerve disorders and cancerous diseases.”

[Figure 1] 3D structure of ATG101-ATG13 complex

The figure on the left shows the structure of ATG101 (shown in yellow) and ATG13 (shown in violet) and how they are connected. The c-terminal of ATG101 (shown in green) in the alpha-helix form is connected to the ATG13 within the protein crystal, as shown on the right.

[Figure 2] Connection of ATG101 c-terminal and PI3K complex components

Without the c-terminal, ATG101’s interaction with PI3K complex components (ATG14, UVRAG, BECN1, PIK3C3) is impaired, in contrast to the original ATG101.