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

TitleDynamically Coupled Residues within the SH2 Domain of FYN Are Key to Unlocking Its Activity.
Publication TypeJournal Article
Year of Publication2016
AuthorsHuculeci, R., E. Cilia, A. Lyczek, L. Buts, K. Houben, M. A. Seeliger, N. van Nuland, and T. Lenaerts
Date Published2016 Nov 01

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.

Alternate JournalStructure
PubMed ID27692963
PubMed Central IDPMC5093032
Grant ListR35 GM119437 / GM / NIGMS NIH HHS / United States
T32 GM008444 / GM / NIGMS NIH HHS / United States
Research group: