For CryoEM, think of taking thousands of copies of the same convoluted complex and scattering them onto the sticky side of a piece of tape. The camera is in a fixed position and takes pictures of these particles, which may have landed right-side-up, on its side, on a point. CryoET, on the other hand, can image the complex in a more natural environment, as it is bound to the cell surface. It takes images from different angles of the complex, similar to a CT scan, where the particle rotates within the instrument. For both techniques, images are then reconstructed into a 3D representation of the complex.
Very different mechanisms identified
The researchers were surprised to find not one, but two ways in which the immune system can be activated: by physical distortion and by cross-activation. In some cases, the configuration of danger signals on a cell’s surface is sparse, and when antibodies bind, the entire complex must physically adjust or distort itself to properly fit. This adjustment of a single complex can set off an immune response. In other situations, where the danger signals are dense, multiple C1 complexes can help activate each other, like a neighbourhood watch system.
This is the first report of two independent ways by which our immune system can be activated. In addition, the combination of CryoEM and CryoET enabled the visualization of details of these interactions that may enable researchers to create more specific therapeutics that can activate, slow down or stop the cascade of signals within our immune system.
Combining CryoEM and CryoET lets researchers see the C1 complex in 3D (coloured model) bound to antibodies in a native state (background).
'Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement'
Deniz Ugurlar, Stuart C. Howes, Bart-Jan de Kreuk, Roman I. Koning, Rob N. de Jong, Frank J. Beurskens, Janine Schuurman, Abraham J. Koster, Thomas H. Sharp, Paul W. H. I. Parren, Piet Gros
Science, 16 February 2018, DOI 10.1126/science.aao4988
This research is part of the interdisciplinary research programme Life Sciences from Utrecht University, and particularly of Science for Life.