A natural product-like molecule called Tantalosin has been identified by researchers. It can inhibit the interaction between two proteins in complexes that reshape cell membranes. The discovery provides a better understanding of how membrane remodeling occurs in human cells and may lead to the development of new drugs. In a study published in PNAS, Umeå researchers describe a natural product-like molecule, Tantalosin, that inhibits interaction between two proteins in complexes that reshape membranes inside the cell. The findings lead to a deeper understanding of how membrane remodelling works in human cells and future development of new drugs.
“Using small molecules as valuable chemical tools for understanding complex biological mechanisms is a good case, as shown in our study. I am pleased to have coordinated a fantastic collaboration with colleagues from UmeÃ¥, Stockholm and Germany,” stated Yaowen Wu, professor at the Department of Chemistry at UmeÃ¥ University.
Cell membranes are composed of lipids and proteins and function as barriers for cells and intracellular organelles. These membranes are dynamic structures that are constantly reshaping. The endosomal sorting complex required for transport (ESCRT) is crucial for membrane remodeling and cellular processes.
The cell is tasked with remodeling membranes inside the cell. The ESCRT machinery assembles at the site in the cell where membranes need deformation and then forms helical protein polymers that can contract and pinch off cell membranes. Previously, Professor Yaowen Wu and his group, in collaboration with Professor Herbert Waldmann’s laboratory at Max Planck Institute Dortmund in Germany, identified a chemical molecule, Tantalosin, that induces a phenotype like autophagy — a self-eating process in the cell. Tantalosin is a synthetic molecule inspired by alkaloids from the medical plant Cinchona. They observed a very interesting phenomenon in the cell.conducted the research. The findings of the study were published in the journal Molecular Cell.
Tantalosin was administered and studied to explore how it operates at a molecular level within the cell. A collaboration with the chemical proteomics core facility at SciLifeLab in Karolinska Institute allowed the team to investigate potential cellular targets of Tantalosin.
The team was surprised to discover that none of the autophagy-related proteins were among the potential targets. However, the IST1 protein in ESCRT complexes was identified and confirmed as the cellular target of Tantalosin. This unexpected link between ESCRT complexes and autophagy was an exciting area for further research, as stated by first author Anastasia Knyazeva.The Department of Chemistry at UmeÃ¥ University recently saw the completion of a doctoral degree. The researchers utilized various biochemical and cell biological methods to characterize the mechanism. Through their study of protein-protein interaction in solution, it was discovered that Tantalosin effectively halts the interaction between IST1 and its binding partner CHMP1B. The two proteins were then examined closely using a transmission electron microscope in collaboration with Kasturika Shankar, a PhD student from Lars-Anders Carlson’s lab at UmeÃ¥ University. It was found that Tantalosin disrupts the process.The paper’s co-first author and postdoctoral fellow at the Department of Chemistry at UmeÃ¥ University, Shuang Li, explained that IST1-CHMP1B filaments were formed in an ordered manner. The researchers also discovered that Tantalosin disrupts the recycling of cell-surface receptors back to the cell surface within the cell. This property may be useful for treating certain types of cancers driven by cell-surface receptors. Additionally, during Tantalosin treatment, the researchers found that the LC3 protein, typically associated with autophagy, is connected to the endosomal membranes. This is an interesting discovery.The researchers did not observe the usual autophagic degradation process. Instead, they discovered that the process follows a different, noncanonical pathway.
“We believe that Tantalosin may be a unique molecule that helps us understand new functions of noncanonical LC3 conjugation to endosomal membranes. We hope that further research will uncover the role of LC3-membrane conjugation and its associated proteins in the process of membrane deformation,” says Anastasia Knyazeva.
