Jülich/Heidelberg, 19 August 2020 - Viruses multiply in the human body by hijacking the functions of cells and using them for their own purposes. Ebola, HIV and other viruses use, among other things, the so-called ESCRT-III complex for this purpose. In healthy cells, this intricate structure made up of numerous protein components is actually used to deform the cell membrane during necessary metabolic processes such as cell division, the formation of cellular organelles - the organs of the cell - or the disposal of waste. Mutations of the complex have been found in frontotemporal dementia, and could also play a role in the development of cancer. ESCRT-III is not only found in humans, but in a very similar form in all animals, plants and fungi.
It is not yet known in detail how exactly the complex deforms the cell membrane and how its individual components are required to interact with each other in order to do so. Scientists at Forschungszentrum Jülich and the European Molecular Biology Laboratory (EMBL) in Heidelberg have now clarified an important detail of its structure. They used what is known as cryo-electron microscopy at the Ernst Ruska-Centre for Microscopy and Spectroscopy with Electrons (ER-C). Together with RWTH Aachen University, the Jülich institute operates high-performance electron microscopes that offer unique insights into the world of atoms, as well as a user facility that provides researchers from science and industry with state-of-the-art instruments, methods and expertise.
Due to its high resolution of 3.2 Å, the method enabled the researchers to see for the first time that one of the subunits of the complex, known as Vps24, assembles itself in the form of elongated, double-helically coiled filaments. Hydrophobic interactions and complementary electrostatic charges in the two strands stabilize the structure. With their investigations, the researchers also provided an explanation for the harmful effect of some mutations of these subunits: they impair the stabilizing interactions. In a test tube, the scientists mixed Vps24 with other ESCRT-III subunits in the presence of biological model membranes and observed how membranes may be deformed in the cell. "However, further studies using cryo-electron microscopy together with other subunits of the ESCRT-III complex are necessary in order to gain an even better understanding of its structure and function, as well as its role in the development of diseases," explains Prof. Carsten Sachse, Director at ER-C, summarizing the results.
Original publication: S. T. Huber et al., Structure and assembly of ESCRT-III helical Vps24 filaments,
Science Advances 19 Aug 2020: Vol. 6, no. 34, eaba4897, DOI: 10.1126/sciadv.aba4897
