TY - JOUR
T1 - The Biased Ligands NGF and NT-3 Differentially Stabilize Trk-A Dimers
AU - Ahmed, Fozia
AU - Zapata-Mercado, Elmer
AU - Rahman, Sanim
AU - Hristova, Kalina
N1 - Publisher Copyright:
© 2020 Biophysical Society
PY - 2021/1/5
Y1 - 2021/1/5
N2 - Trk-A is a receptor tyrosine kinase (RTK) that plays an essential role in the development and functioning of the nervous system. Trk-A is expressed in neurons and signals in response to two ligands, NGF and neurotrophin-3 (NT-3), with very different functional consequences. Thus, NGF and NT-3 are “biased” ligands for Trk-A. Because it has been hypothesized that biased RTK ligands induce differential stabilization of RTK dimers, here, we seek to test this hypothesis for NGF and NT-3. In particular, we use Förster resonance energy transfer (FRET) and fluorescence intensity fluctuation spectroscopy to assess the strength of Trk-A interactions and Trk-A oligomer size in the presence of the two ligands. Although the difference in Trk-A behavior in response to the two ligands has been previously attributed to differences in their binding to Trk-A in the endosomes at low pH, here, we further show differences in the stabilities of the NGF- and NT-3-bound Trk-A dimers in the plasma membrane and at neutral pH. We discuss the biological significance of these new findings and their implications for the design of Trk-A ligands with novel functionalities.
AB - Trk-A is a receptor tyrosine kinase (RTK) that plays an essential role in the development and functioning of the nervous system. Trk-A is expressed in neurons and signals in response to two ligands, NGF and neurotrophin-3 (NT-3), with very different functional consequences. Thus, NGF and NT-3 are “biased” ligands for Trk-A. Because it has been hypothesized that biased RTK ligands induce differential stabilization of RTK dimers, here, we seek to test this hypothesis for NGF and NT-3. In particular, we use Förster resonance energy transfer (FRET) and fluorescence intensity fluctuation spectroscopy to assess the strength of Trk-A interactions and Trk-A oligomer size in the presence of the two ligands. Although the difference in Trk-A behavior in response to the two ligands has been previously attributed to differences in their binding to Trk-A in the endosomes at low pH, here, we further show differences in the stabilities of the NGF- and NT-3-bound Trk-A dimers in the plasma membrane and at neutral pH. We discuss the biological significance of these new findings and their implications for the design of Trk-A ligands with novel functionalities.
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U2 - 10.1016/j.bpj.2020.11.2262
DO - 10.1016/j.bpj.2020.11.2262
M3 - Article
C2 - 33285113
AN - SCOPUS:85098534763
SN - 0006-3495
VL - 120
SP - 55
EP - 63
JO - Biophysical journal
JF - Biophysical journal
IS - 1
ER -