Dynamically Coupled Residues within the SH2 Domain of FYN Are Key to Unlocking Its Activity.

Radu Huculeci, Elisa Cilia, Agatha Lyczek, Lieven Buts, Klaartje Houben, Markus A Seeliger, Nico van Nuland, Tom Lenaerts

Journal: Structure (London, England : 1993) 2017;24(11):1947-1959

PMID: 27692963

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Abstract

Src kinase activity is controlled by various mechanisms involving a coordinated movement of kinase and regulatory domains. Notwithstanding the extensive knowledge related to the backbone dynamics, little is known about the more subtle side-chain dynamics within the regulatory domains and their role in the activation process. Here, we show through experimental methyl dynamic results and predicted changes in side-chain conformational couplings that the SH2 structure of Fyn contains a dynamic network capable of propagating binding information. We reveal that binding the phosphorylated tail of Fyn perturbs a residue cluster near the linker connecting the SH2 and SH3 domains of Fyn, which is known to be relevant in the regulation of the activity of Fyn. Biochemical perturbation experiments validate that those residues are essential for inhibition of Fyn, leading to a gain of function upon mutation. These findings reveal how side-chain dynamics may facilitate the allosteric regulation of the different members of the Src kinase family.

Address: Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel, Belgium; Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussel, Belgium.; MLG, Départment d'Informatique, Université Libre de Bruxelles, Boulevard du Triomphe CP212, 1050 Brussels, Belgium; Interuniversity Institute of Bioinformatics Brussels (IB(2)), ULB-VUB, La Plaine Campus, Boulevard du Triomphe CP 263, 1050 Brussels, Belgium.; Department of Pharmacological Sciences, Stony Brook University School of Medicine, BST 8-140, Stony Brook, NY 11794-8651, USA.; NMR spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands.; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel, Belgium; Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussel, Belgium. Electronic address: [email protected].; MLG, Départment d'Informatique, Université Libre de Bruxelles, Boulevard du Triomphe CP212, 1050 Brussels, Belgium; Interuniversity Institute of Bioinformatics Brussels (IB(2)), ULB-VUB, La Plaine Campus, Boulevard du Triomphe CP 263, 1050 Brussels, Belgium; AI-lab, Vakgroep Computerwetenschappen, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: [email protected].

DOI: 10.1016/j.str.2016.08.016