It was long believed that proteins need to be well structured to function, but during the last decade it has become clear that disorder is often crucial for function. Now, a research team at Uppsala University has shed light on how such disordered proteins interact with each other.
Going from a peculiarity to an intense research field in less than a decade, protein disorder has emerged as a crucial property governing for example numerous protein-mediated signalling pathways in the cell. Several theories have been put forward to explain why so many proteins are disordered, but there is a paucity of experimental data to support the theories. The Uppsala team has addressed questions about how disordered proteins interact and how fast.
The results were published in three consecutive papers, in the Journal of the American Chemical Society, the Journal of Molecular Biology and the Journal of Biological Chemistry, respectively. "We started with short disordered protein fragments, then looked at bigger disordered regions and finally at completely disordered protein domains, which are independent modules of larger proteins. We found that the rate of interaction is in the same range as for the well-studied folded proteins" says Per Jemth who lead the study.
Another interesting observation is that the initial interaction between a disordered protein and its binding parner is quite non-specific, like a one-size-fits-all garment. Specific interactions, which are salient features of protein-protein interactions (like a tailor-made suit), appear later, at the end of the association. At this point the disordered protein is no longer disordered but has acquired a well-defined structured, tightly bound to its partner.
"It also surprised us that the specific recognition takes such a long time to develop" says Jakob Dogan who conducted the work in the third paper. "This slow step may be a result of the fact that disordered proteins often have multiple binding partners. Each partner requires a distinct shape of the disordered protein and the interaction cannot be optimized for one particular partner."
The results highlight fundamental principles regarding disordered proteins. "Disordered proteins are very common in central cellular signalling pathways and it's likely that they will be drug targets in the future, since they are often associated with neurodegenerative diseases and cancer. But right now we're just trying to understand the basics" Per Jemth concludes.
The project was funded by the Swedish Research Council and the Human Frontiers Science Programme.
For more information contact Per Jemth, e-mail: Per.Jemth@imbim.uu.se, phone:+46-18-471 4557.
Haq, S. R., Chi, C. N., Bach, A., Dogan, J., Engström, Å., Hultqvist, G., Karlsson, A., Lundström, P., Montemiglio, L. C., Strømgaard, K., Gianni, S., and Jemth, P. (2012) Side chain interactions form late and cooperatively in the binding reaction between disordered peptides and PDZ domains. J. Am. Chem. Soc. 134, 599-605.
Karlsson, A., Chi, C. N., Engström, Å., and Jemth, P. (2012) The transition state for coupled folding and binding for a flexible beta finger. J. Mol. Biol. 417, 253-261. In Press
Dogan, J., Schmidt, T., Mu, X., Engström, Å., and Jemth, P. (2012) Fast association and slow transitions in the interaction between two intrinsically disordered protein domains. J. Biol. Chem.
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