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NMR Spectroscopy of very large complexes: the atomic details of the mRNA degradation machinery

Final Report Summary - MRNA-DECAY (NMR Spectroscopy of very large complexes: the atomic details of the mRNA degradation machinery)

Our current view of protein structures is biased by static three-dimensional images. Biomolecules are, however, highly dynamic and constantly undergo structural rearrangements to perform biological tasks. We have addressed this important dynamic aspect for the enzymes and adaptor proteins that are involved in mRNA degradation.

On one hand, we identified and quantified conformational changes in the Dcp1:Dcp2 mRNA decapping complex, in the DcpS decapping enzyme and in the exosome complex. These motions were to a large degree previously undetected and we have established that these play an important role for regulating catalytic activity. These results thus underscore the importance of extending our understanding of biomolecular structures such that a complete knowledge of all possible structural states and the rates with which these states interchange is obtained.

On the other hand, we have identified how dynamic interactions between proteins are able to induce cellular liquid-liquid phase separation events. Such events are now well recognized to aid the organization of the cellular space into regions with specialized functions. We have found that the network of interactions that drives these phase separations is highly diverse and includes interactions between folded protein domains, intrinsically disordered regions and RNA. Structurally, we have shown that the proteins remain in a native conformation inside the high-density protein phase, but that, enzymatic activity can be significantly reduced.

In summary, our work has shed unique insights into molecular mechanisms that go beyond static images.