New approaches against fungal infections discovered
A research team from Münster and Athens has used state-of-the-art cryo-electron microscopy to decode the structure of a key fungal transporter
They are the cell’s ‘gatekeepers’: specialised proteins, known as transporters, selectively control which substances enter a cell and which do not. Researchers at the University of Münster and the National and Kapodistrian University of Athens have investigated these transporters in a specific case: the UapA transporter of the model fungus Aspergillus nidulans. The findings are not only relevant to cell biology but could also offer new approaches to treating fungal infections.
These transporters are essential for pathogenic fungal species to bring important nutrients into the cell. Of particular relevance is the fact that homologous transporters are found in humans. These are responsible for the co-transport of vitamin C and sodium ions. Research into the UapA transporter of the model fungus can therefore also provide insights into the structure and function of human transporters. It is also important to note that several Aspergillus species are pathogens capable of causing severe, life-threatening infections in immunocompromised individuals. “Investigating and understanding these transport processes is therefore of particular biomedical significance,” emphasises Prof. Christos Gatsogiannis, who is leading the research at the University of Münster with his team.
The research findings suggest that UapA functions via a specialised ‘elevator-type’ transport mechanism. In this mechanism, the protein consists of a relatively rigid scaffold domain (the ‘shaft’), which is embedded in the membrane, and a mobile transport domain (the ‘elevator’), which binds the substrate. During transport, this ‘elevator’ moves along the scaffold, carrying the substrate from the outside of the cell into the cytoplasm. This process requires precise coordination with membrane lipids and surrounding water molecules. Until now, the molecular basis of this process was poorly understood due to a lack of structural information.
With its new study, the research team has made a significant advance in elucidating this transport mechanism. The research group led by Prof. Christos Gatsogiannis at the Institute of Medical Physics and Biophysics and the Centre for Soft Nanoscience at the University of Münster achieved a decisive breakthrough: using state-of-the-art cryo-electron microscopy, they succeeded in imaging UapA in two different states. The structures were determined at an exceptional resolution of 2.05 Å – one of the highest resolutions ever achieved using a structural determination method for a eukaryotic membrane transporter. This level of detail allows the visualisation of the protein’s architecture, as well as individual water molecules and the surrounding membrane lipids. One of the most striking findings concerns the N-terminal region of the protein: until now, it was assumed that this region had no fixed structure. However, the new data show that the region fulfils a dual function: it helps the transporter to fold correctly and reach the cell surface. It also plays a role in regulating how the transporter functions.
The findings are fully consistent with genetic and functional studies carried out by the research group led by Prof. George Diallinas at the Institute of Biology, National and Kapodistrian University of Athens. They thus expand our understanding of how UapA functions. Transporters such as UapA can be used, amongst other things, for antifungal drugs – that is, medicines used to treat fungal infections – to enable them to enter fungal cells. A deeper understanding of their structure and function could therefore contribute to the development of new therapeutic strategies against fungal infections.
Journal
Proceedings of the National Academy of Sciences
Article Title
Cryo-EM of the eukaryotic purine transporter UapA demonstrates intramolecular and lipid regulation of transport
Data may reveal the hidden communication of pathogenic fungi
Extracellular vesicles, or EVs, are small particles that transport proteins, lipids and nucleic acids and play an important role in communication between cells. However, much less is known about EVs released by fungi. It remains unclear how they influence the immune system and what role they play in the development of invasive infections.
Supported by nearly €6.8 million from the Novo Nordisk Foundation, the CLEVER project aims to create the first comprehensive fungal EV atlas. The project is led by Attila Gácser, head of the Institute of Biology at the University of Szeged, who has studied fungi for more than 30 years and is strongly committed to encouraging young people to pursue careers in the natural sciences. The researchers will investigate vesicles produced by fungi belonging to the Candida, Aspergillus and Cryptococcus genera, while also working to standardise the methods used for their isolation and analysis.
Krisztina Buzás, head of the Department of Immunology at the University of Szeged and a researcher at HUN-REN BRC, will play a key role in the project’s EV-related research activities in Szeged. From the HUN-REN BRC EV research group, Mátyás Bukva, Tímea Böröczky, Gabriella Dobra, Ágnes Czibula, Emma Balog and Judit Danis will also take part in the work. The group will primarily contribute to the processing, comparison and interpretation of large volumes of molecular data generated from different fungal species and experimental systems.
The collaboration also brings together researchers from Semmelweis University, Aarhus University, the Fiocruz Carlos Chagas Institute in Brazil, ELI ALPS and research institutions in the United States. Participants include Edit Buzás, Lars Østergaard, Peter Nejsum, Karen Lausch, Marcio Lourenço Rodrigues and Norbert Pardi.
The project’s Scientific Advisory Board is chaired by Nobel Prize-winning researcher Katalin Karikó, professor at the University of Szeged. The board also includes Arturo Casadevall, Carlos Morel and Katrien Lagrou.
The programme combines Szeged’s internationally recognised expertise in fungal research and extracellular vesicle biology. Its aim is to uncover how pathogenic fungi communicate with the human body and to determine how these still poorly understood processes could eventually contribute to more accurate diagnosis and improved treatment of fungal infections.
No comments:
Post a Comment