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 language | English |
|---|---|
| Pages (from-to) | 17088-17094 |
| Number of pages | 7 |
| Journal | Journal of Biological Chemistry |
| Volume | 277 |
| Issue number | 19 |
| DOIs | |
| State | Published - May 10 2002 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors
AU - Yan, Kelley S.
AU - Kuti, Miklos
AU - Yan, Sherry
AU - Mujtaba, Shiraz
AU - Farooq, Amjad
AU - Goldfarb, Mitchell P.
AU - Zhou, Ming Ming
PY - 2002/5/10
Y1 - 2002/5/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0037053398&partnerID=8YFLogxK
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U2 - 10.1074/jbc.M107963200
DO - 10.1074/jbc.M107963200
M3 - Article
VL - 277
SP - 17088
EP - 17094
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 19
ER -