FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors

Kelley S. Yan, Miklos Kuti, Sherry Yan, Shiraz Mujtaba, Amjad Farooq, Mitchell P. Goldfarb, Ming Ming Zhou

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Membrane-anchored adaptor proteins FRS2α/β (also known as SNT-1/2) mediate signaling of fibroblast growth factor receptors (FGFRs) and neurotrophin receptors (TRKs) through their N-terminal phosphotyrosine binding (PTB) domains. The FRS2 PTB domain recognizes tyrosine-phosphorylated TRKs at an NPXpY (where pY is phosphotyrosine) motif, whereas its constitutive association with FGFR involves a receptor juxtamembrane region lacking Tyr and Asn residues. Here we show by isothermal titration calorimetry that the FRS2α PTB domain binding to peptides derived from TRKs or FGFR is thermodynamically different. TRK binding is largely enthalpy-driven, whereas the FGFR interaction is governed by a favorable entropic contribution to the free energy of binding. Furthermore, our NMR spectral analysis suggests that disruption of an unstructured region C-terminal to the PTB domain alters local conformation and dynamics of the residues at the ligand-binding site, and that structural disruption of the β8-strand directly weakens the PTB domain association with the FGFR ligand. Together, our new findings support a molecular mechanism by which conformational dynamics of the FRS2α PTB domain dictates its association with either fibroblast growth factor or neurotrophin receptors in neuronal development.

Original languageEnglish
Pages (from-to)17088-17094
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number19
DOIs
StatePublished - May 10 2002
Externally publishedYes

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Phosphotyrosine
Fibroblast Growth Factor Receptors
Conformations
Nerve Growth Factor Receptors
Association reactions
Ligands
Calorimetry
Titration
Spectrum analysis
Free energy
Tyrosine
Enthalpy
Binding Sites
Nuclear magnetic resonance
Membranes
Peptides

ASJC Scopus subject areas

  • Biochemistry

Cite this

FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors. / Yan, Kelley S.; Kuti, Miklos; Yan, Sherry; Mujtaba, Shiraz; Farooq, Amjad; Goldfarb, Mitchell P.; Zhou, Ming Ming.

In: Journal of Biological Chemistry, Vol. 277, No. 19, 10.05.2002, p. 17088-17094.

Research output: Contribution to journalArticle

Yan, Kelley S. ; Kuti, Miklos ; Yan, Sherry ; Mujtaba, Shiraz ; Farooq, Amjad ; Goldfarb, Mitchell P. ; Zhou, Ming Ming. / FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 19. pp. 17088-17094.
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