Proteins in Motion (2009)

![Figure][1] 

CREDIT: TOKURIKI AND TAWFIK

Three years ago, A special issue of Science (14 April 2006) focused on new tools used to observe proteins at work. The view that has emerged is that of an intricate ballet: Individual proteins are in constant motion, sampling an ensemble of different conformations and perhaps changing interaction partners as they play their part in a particular biological process.

How do these dynamics affect function? The conformational space that a protein can explore can be described by an energy landscape, in which different conformations are populated based on their energies, and rates of interconversion are dependent on the energy barriers between states. The landscape, and thus the relative populations of conformational states, can be modulated, for example, by interactions with other proteins or by covalent modifications such as phosphorylation. Smock and Gierasch (p. 198) present examples that illustrate how these dynamic properties allow proteins to transmit signals by acting as switches and transducers. Factors that modulate the energy landscape might also disrupt protein function. Traditional structure-based drug design has focused on targeting a static active site. More opportunities for drug discovery come from considering the entire free-energy landscape of a protein. Lee and Craik (p. [213][2]) provide examples of allosterically active drugs that are either on the market or in late clinical testing. These lay the groundwork for future efforts to discover drugs that act by trapping proteins in an inactive state; such drugs can act to inhibit enzyme activity or to inhibit an interaction on a signaling pathway.

The proficiency and specificity of proteins are characteristics that might reasonably be associated with a lack of versatility, but proteins also adapt, as evidenced by the serious problem of drug resistance. Tokuriki and Tawfik (p. [203][3]) suggest that the conformational diversity of proteins makes them evolvable. Minor conformers may mediate alternate functions, and mutations could shift the conformational equilibrium to favor these conformers and so increase the level of the alternate function. The scale at which protein dynamics influence function goes beyond the molecular and cellular levels to the tissue level. Engler et al. (p. 208) describe how dynamic cell-cell and cell-extracellular matrix adhesion complexes respond to soluble factors and to mechanical cues to form and maintain differentiated tissues.

In Presentations, Perspectives, Meeting Reports, and Research Articles, Science Signaling ([www.sciencemag.org/sciext/proteindynamics][4]) highlights conformational changes in G protein-coupled receptor signaling (Houslay) and allosteric regulation in immune cell signaling (Chakraborty et al. ), as well as providing insight into how pathogens exploit host protein interactions to their advantage (Liu et al. ) and mechanisms by which the subcellular trafficking of proteins can influence cellular behavior (Pouille et al. and Dustin).

As progress continues in identifying proteomes and mapping interaction networks, the challenge is to also understand the molecular-level protein dynamics that allow proteins to act as receivers, switches, and relays and facilitate communication from the subcellular level through to the cell and tissue levels.

 [1]: pending:yes
 [2]: /lookup/doi/10.1126/science.1169378
 [3]: /lookup/doi/10.1126/science.1169375
 [4]: http://www.sciencemag.org/sciext/proteindynamics