The description of the molecular basis of the interactome, is expected to provide a comprehensive portrayal of the overall interaction structure of an organism's proteome, thereby representing one of the major challenges for structural biology in the coming decade. A deep understanding of the rules governing molecular recognition processes is crucial to rational designing drugs and its pharmacological and biotechnological implications are quite noteworthy. Allostery is a fundamental property embedded in protein structure and dynamics. Even in proteins that are not known to be allosterically regulated, allosteric sites can easily be introduced through random mutagenesis.
Studying internal communication mechanisms and individual macromolecular interactions is only relevant if they can be put into their biological context. This biological context usually involves an interaction network. Living cells feature complex protein networks involved in information signal transfer and processing events, commonly named as signal transduction pathways finely modulated by protein-protein interactions. Such networks generate emerging properties that cannot be predicted from the sum of the activities of the individual components of the network. Understanding networks thus requires studying multi-component interactions and is possible in detail only for the smallest networks consisting only of a few components.
Scientific questions and long-term objectives
Complex protein networks involved in information transfer and processing events are finely modulated by protein-protein interactions. To understand fundamental aspects of regulation at the protein level such as co-operativity and allostery, including allosteric communication between intrinsically disordered domains, the long-term objective is to understand the complex interplay between structure, dynamics and energetics of internal pathways proteins use for site-to-site communication. These aspects will be tackled by NMR in combination with other biophysical techniques and theoretical methods to quantify information exchange.
- The structure of TAX1BP1 UBZ1+2 provides insight into target specificity and adaptability. (J Mol Biol, 426, 674-90, 2014)
- Allostery and intrinsic disorder mediate transcription regulation by conditional cooperativity. (Cell, 142, 101-11, 2010)
- Accurate characterization of weak macromolecular interactions by titration of NMR residual dipolar couplings: application to the CD2AP SH3-C:ubiquitin complex. (Nucleic Acids Res, 37, e70, 2009)
- Transient protein encounters characterized by paramagnetic NMR (Chemical Science, 5, 4227-4236, 2014)