Identifying the mechanisms involved in transducing binding information through SH3-SH2 supradomains and their role in regulating the activity of members of the family of Src kinases

Communication is essential at all biological scales. Our cells have been rigged with communication systems that allow them to respond properly to environmental cues. These systems, or signaling pathways, are composed of different proteins, whose activity is regulated by other proteins. This intricate regulatory system ensures that cells provide the right response, both in kind and magnitude. Errors in regulation often result in diseases. Src kinases (SFK) are typical examples of proteins involved in signaling pathways. To control their activity, evolution has come up with an exquisite solution. Two modular parts of these proteins are responsible for regulating the activity of the third module, which performs the actual function of the kinase. Here, we aim to provide new insights into how the switching between active and inactive SFK may occur: we examine how dynamic information, induced by binding peptides to the regulating domains, flows through their structure and influences SFK activity. Our prior research suggests that a particular locking dynamics mediated by specific residue sidechains in those modules may play an essential role. This project aims to validate this hypothesis. The results produced here will allow us to build methods capable of identifying regulatory hotspots in proteins, will provide explanations as to why certain residues are involved in disease and, more ambitiously, will allow us to design proteins with specific regulatory capabilities.

 

People

Anmol Gautam, Wim Vranken, Peter Tompa, Tom Lenaerts

 

Partners

VUB, VIB

 

Publications

Radu Huculeci, Abel Garcia-Pino, Lieven Buts, Tom Lenaerts and Nico van Nuland (2015) Structural insights into the intertwined dimer of Fyn SH2. Protein Science 24(12):1964-78
Radu Huculeci, Elisa Cilia, Lieven Buts, Klaartje Houben, Nico van Nuland and Tom Lenaerts (2016) Dynamically coupled residues within the SH2 domain of FYN are key to unlock its activity. Structure 24(11):1947-1959
Ana Zafra Ruano, Elisa Cilia, José Couceiro, Javier Ruiz Sanz, Joost Schymkowitz, Frederic Rousseau, Irene Luque and Tom Lenaerts (2016) From binding-induced dynamic effects in SH3 structures to evolutionary conserved sectors. PLOS Computational Biology 12(5):e1004938
Radu Huculeci, Fabien Kieken, Abel Garcia-Pino, Lieven Buts, Tom Lenaerts and Nico van Nuland (2017) Structural characterization of monomeric/dimeric state p59fyn SH2 domain. In K.Machida and B. Liu (Ed.) SH2 Domains: methods and protocols. Methods in Molecular Biology. Springer pp 257-267.
Kieken, F., Loth, K., van Nuland, N., Tompa, P., & Lenaerts, T. (2018). Chemical shift assignments of the partially deuterated Fyn SH2–SH3 domain. Biomolecular NMR assignments, 12(1):117-122.

 

Extra info

Structures and dynamic data produced in this project
NMR spectroscopy data Fyn SH3-SH2 tandem : http://www.bmrb.wisc.edu/data_library/summary/index.php?bmrbId=27165