Sending Signals Dynamically

Abstract

Proteins mediate transmission of signals along intercellular and intracellular pathways and between the exterior and the interior of a cell. The dynamic properties of signaling proteins are crucial to their functions. We discuss emerging paradigms for the role of protein dynamics in signaling. A central tenet is that proteins fluctuate among many states on evolutionarily selected energy landscapes. Upstream signals remodel this landscape, causing signaling proteins to transmit information to downstream partners. New methods provide insight into the dynamic properties of signaling proteins at the atomic scale. The next stages in the signaling hierarchyhow multiple signals are integrated and how cellular signaling pathways are organized in space and time-present exciting challenges for the future, requiring bold multidisciplinary approaches.Transmission of signals between cells, within cells, and from the extracellular environment to the cellular interior is essential to life. In recent years, we have gained tremendous knowledge of the interacting networks that act as communication pathways for cellular signaling, culminating with extensive maps of "interactomes" based on genetic and physical interaction data [e.g., (1)]. Yet we know far less about how signals are passed from one component of a network to another. This puzzle can be viewed at the level of the protein machines that make up signaling networks: How does information, generally mediated by a binding interaction or a covalent modification, get relayed to the downstream member of the pathway?It is increasingly apparent that signaling relies on the intrinsic dynamic properties of proteins and that proteins relay signals by shifting among different fluctuating energy states in response to one or more inputs. This emerging view of signaling raises many compelling questions: What is the genetic information that encodes the functionally productive dynamic properties of a protein? How do individual protein domains cooperate to form signaling pathways? How are signals integrated in multicomponent interconnecting networks? How do the dynamics of signaling proteins ultimately determine the response times of cells to signals and the time scales for signal propagation? We are beginning to develop the methods and principles to address these questions, but many challenges lie ahead. Our ability to develop therapeutic modulators of signaling and to reengineer cellular communication pathways will rely on progress in this fascinating but complex arena.The intrinsic motions of proteins are determined by the covalent and noncovalent restraining forces that hold them together. The result is a symphony of dynamic modes oscillating at frequencies from picoseconds to milliseconds or even seconds. Tweaking a protein by a binding interaction or chemical modification alters this symphony, either gently changing its pitch or abruptly shifting the collective harmony. Just as the ability of a protein to fold is now understood to be best described by an "energy landscape," w...

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