Cells in the human body must adapt their protein balance to certain situations, such as the availability of iron or an infection. These adaptations occur through a complex process in which proteins that are no longer needed or that are toxic are tagged for destruction by attaching a small protein called ubiquitin to them. This marking of a protein for destruction by tagging with ubiquitin is carried out by Cullin-RING Ligases, or 'CRLs' for short. Therefore, CRLs can be considered as 'destroyers' of specific protein molecules.
, essentially a 3D molecular photograph, showing how the antibody can capture NEDD8 attached to almost all CRLs, only when a CRL is switched on to allow ubiquitin tagging of proteins to be destroyed. Thus, the synthetic antibody is an activity-based probe, or a"molecular radar," that can detect which CRLs are activated to tag their target proteins for destruction.
The scientists in the departments of Brenda Schulman and Matthias Mann at the MPI of Biochemistry then developed the second step of the new method to find out which ones of the entire fleet of CRLs are switched on under normal cellular conditions, and which are switched on to adapt to changing cellular needs. The CRL
bound to the antibody, i.e., the active ones, were removed from the cells and collected in order to use state-of-the-art mass spectrometry to measure which and how many CRLs were active in the cells at a specific point in time.In the current study, the authors could identify which CRLs are turned on in response to iron, and which are turned on by cellular signs of inflammation. The authors also studied CRLs that are turned on for the action of so-called"degrader" drugs.
The new method showed that the available amount of certain CRLs varies in different cell types, which influences the effectiveness of the degrader drugs. The more of the CRL"destroyer" already switched on in a cell, the faster a degrader molecule can cause the disease causing protein to be eliminated.The researchers also teamed up with Peter Murray's laboratory at the MPI of Biochemistry to study the active CRLs in cells called macrophages.
balance and their involvement in pathophysiological states, which may guide the use of CRLs in the development of new therapies in the future.Lukas T. Henneberg et al, Activity-based profiling of cullin–RING E3 networks by conformation-specific probes,
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