title: FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors.
abstract: Membrane-anchored adaptor proteins FRS2alpha/beta (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 FRS2alpha 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 beta8-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 FRS2alpha PTB domain dictates its association with either fibroblast growth factor or neurotrophin receptors in neuronal development.
authors.affiliation: Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York, New York 10029, USA.
authors.forename: Kelley S
authors.initials: KS
authors.lastname: Yan
authors.forename: Miklos
authors.initials: M
authors.lastname: Kuti
authors.forename: Sherry
authors.initials: S
authors.lastname: Yan
authors.forename: Shiraz
authors.initials: S
authors.lastname: Mujtaba
authors.forename: Amjad
authors.initials: A
authors.lastname: Farooq
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Goldfarb
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D002151:Calorimetry; D018076:DNA, Complementary / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D055504:Insulin Receptor Substrate Proteins; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010750:Phosphoproteins / Q000737:chemistry*; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D013816:Thermodynamics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018076:DNA, Complementary; C106534:FRS2 protein, human; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D008024:Ligands; D008565:Membrane Proteins; D010455:Peptides; D010750:Phosphoproteins; D017475:Receptors, Nerve Growth Factor; D005346:Fibroblast Growth Factors