Unravelling the allosteric effects of SHP2’s SH2 domains in the JAK/STAT pathway through NMR relaxation experiments

Lucia Rubio Fernandez, Radu Ion Huculeci, Sophie Vanwetswinkel, Tom Lenaerts, Nico Van Nuland

Research output: Contribution to journalEditorial

Abstract

SHP2 is tyrosine phosphatase involved in the attenuation of the cytokine-induced JAK/STAT signalling pathway. The protein binds through its two SH2 domains to phosphotyrosines located on the intracellular part of the implicated receptors. Although both SH2 domains bind peptides containing phosphorylated tyrosines, they seem to experience different dynamical effects in the activation process: The N-SH2 domain, which blocks directly the active site of the PTP domain through its D-E loop and connected ?-strands, experiences a functional allosteric effect which induces it to release the active site when binding to a phosphotyrosine peptide. This dynamic behaviour, is not observed for the neighbouring C-terminal SH2 (C-SH2), which links the N-SH2 to the phosphatase domain. Even more, this behaviour is clearly different from other SH2 family members like those involved in activation of kinases like Src and Fyn. To understand the dynamic differences between these SH2 domains our goal is to examine the changes in sidechain methyl dynamics measurements [1] caused by binding phosphorylated peptide related to intracellular part of EpoR and TpoR. As a first step in this investigation we are resolvng the structures of both SH2 domains of human SHP2 and study the binding effects through a range of NMR relaxation experiments, producing additionally novel NMR ensembles of both domains in bound and unbound form. Secondly we will examine how this information corresponds to the data recently acquired from the SH2 domain of Fyn. Together these results will allow us to show the initial dynamics differences and similarities inherent to this family of protein domains.

[1] Fuentes, E.J., C.J. Der, and A.L. Lee, Ligand-dependent dynamics and intramolecular signaling in a PDZ domain. J Mol Biol, 2004. 335(4): p. 1105-15.
Original languageEnglish
JournalUnknown Journal
Publication statusPublished - 14 Sep 2011

Keywords

  • SHP2
  • SH2
  • NMR

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