UNIST·GIST, World's First Determination of Lysosomal Transport Protein Complex Structure

The mechanism of action of a protein that regulates the genes of the cell organelle responsible for digestion during eukaryotic cell division, the ‘lysosome,’ has been revealed for the first time in the world, attracting attention.

Professor Changwook Lee’s team from the Department of Life Sciences at UNIST conducted joint research on the gene regulation principle of the ‘lysosome’ together with Professor Youngsoo Jeon’s team from the Department of Life Sciences at GIST.

The research team used a yeast model to discover for the first time in the world that Vac 8, a lysosomal protein involved in autophagy during cell division, forms a complex with its binding partner protein Vac 17 to suppress autophagy and regulate lysosome transport to the divided cells.

UNIST stated that this related research is expected to become an important cornerstone for therapeutic studies on cancer, chronic diseases, and other conditions caused by abnormal cell division in the future.

Cell division is an indispensable element for the survival of living organisms such as humans. Therefore, it is precisely regulated by many intracellular mechanisms.

In particular, the regulation of autophagy within the cell is very important for complete and safe cell division. If organelles and components of dividing cells are degraded through autophagy, normal division into daughter cells cannot occur.

The lysosomal protein Vac 8 is known to selectively regulate autophagy by forming complexes with various binding partners. It also binds with Vac 17 and Myo2 proteins to participate in lysosome transport during cell division.

Vac 8 forms a triple complex with Vac 17 and Myo2, and this complex transports lysosomes from the mother cell to the daughter cell along actin proteins, which act as intracellular roads.

Previous studies revealed that the formation of a complex between Vac 8 and Vac 17 proteins is important for lysosome transport, but molecular-level research on how Vac 8 suppresses autophagy and performs lysosome transport functions within the cell had not been elucidated.

The research team determined the high-resolution structure of the Vac 8-Vac 17 complex for the first time in the world using X-ray crystallography. The complex forms two binding interfaces.

In particular, the team identified amino acids directly involved in interface formation, and in yeast with mutations in these amino acids of Vac 8 and Vac 17, lysosomes failed to move to daughter cells during cell division. This directly proved that Vac 8 regulates lysosome transport.

Protein crystal structures of Vac8-Vac17.

Additionally, this study demonstrated that the quaternary structure formed when Vac 8 forms a complex with specific binding partners distinguishes and regulates autophagy and lysosome transport.

The research team revealed that this structural difference is regulated by the ARM domain and the N-terminal H1 helix included in Vac 8.

When the Vac 8-Vac 17 complex forms, Vac 17 binds to the H1 helix of Vac 8, preventing the H1 helix from separating from the ARM domain, thereby inhibiting the formation of autophagy-inducing complexes (Vac 8-Nvj1, Vac 8-Atg13). This means that autophagy is suppressed and lysosome transport occurs during cell division.

Professor Changwook Lee of the Department of Life Sciences said, “This study is an important example showing how the suppression of autophagy activity and lysosome transport during cell division can be regulated by a single protein,” adding, “It will be an important cornerstone for research on diseases related to cell division, such as cancer and various chronic diseases.”

The results of this study were published in the April 24 issue of the Proceedings of the National Academy of Sciences (PNAS). The research was supported by the Ministry of Science and ICT and the National Research Foundation of Korea (Leading Research Center Support Project, Mid-career Researcher Support Project, Bio-convergence Core Technology Development Project).

This content was produced with the assistance of AI translation services.