Researchers have discovered the atomic structure of a protein which controls how cells make decisions, and which may cause skin disease and predispose cells to cancer, challenging received wisdom about how it works. The new results suggest that tiny movements, on the scale of a millionth of a millimetre, effectively switch the protein on and off, driving changes in cell behaviour.
Through a large interdisciplinary collaboration funded by the Medical Research Council, Cancer Research UK, the Wellcome Trust and the Royal Society, researchers at Birkbeck, UCL and Cambridge worked together to use advanced techniques from biology, physics, and computational science to show what the protein, IKK-gamma, looks like and how it moves. From this, they proposed how it initiates different cellular behaviours.
IKK-gamma is long and flexible, and as such standard approaches such as X-ray crystallography could only show the structure of small fragments. To overcome this, the team used a magnetic resonance technique whereby molecular sized magnets were attached to the protein as labels. When placed into a strong magnetic field, pairs and quartets of these labels respond to microwaves, and allow the distances between them to be measured. By putting sets of labels in different locations in the protein the distances between different parts of the protein could be calculated. The results were then used to choose between different proposed structures until only one compatible structure remained.
Professor Chris Kay, from UCL, commented that “the study shows how powerful interdisciplinary work can be. None of the approaches on their own could give us this much insight into how IKK-gamma works.”
Dr Ben Hall, from the MRC-Cancer Unit at University of Cambridge added “Through bringing together state of the art modelling approaches with experiment we’ve been able to show how small changes may tweak the structure of the protein, which in turn leads to whole-cell and even tissue behaviour.”
This work gives an unprecedented insight into how a single protein may control large numbers of signalling networks. These findings also suggest how proteins from other biological systems with similar structures integrate information in the cell.
Commenting on the findings, which were published this month in the Journal of Biological Chemistry, Dr. Ben Hall said: “This is the most complete view of IKKG ever achieved. The combination of both the level of detail seen and the completeness of the data are the first step to thinking about how understand how IKKG goes wrong in different diseases, and how treatments may be designed in future to correct these mistakes.”
Bagnéris C, Rogala KB, Baratchian M, Zamfir V, Kunze MB, Dagles S, Pirker KF, Collins MK, Hall BA, Barrett TE, Kay CW.Probing the Solution Structure of IκB Kinase (IKK) Subunit γ and its Interaction with Kaposi's Sarcoma Associated Herpes Virus Flice Interacting Protein and IKK Subunit β by EPR Spectroscopy..J Biol Chem. 2015 May 14. pii: jbc.M114.622928. [Epub ahead of print].
Video: Dr Ben Hall discusses his research. Ben_H_00015 (4)