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Structural basis of SNT PTB domain interactions with distinct neurotrophic receptors
C Dhalluin1, K S Yan, O Plotnikova
1Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York 10029, USA.
Abstract:
SNT adaptor proteins transduce activation of fibroblast growth factor receptors (FGFRs) and neurotrophin receptors (TRKs) to common signaling targets. The SNT-1 phosphotyrosine binding (PTB) domain recognizes activated TRKs at a canonical NPXpY motif and, atypically, binds to nonphosphorylated FGFRs in a region lacking tyrosine or asparagine. Here, using NMR and mutational analyses, we show that the PTB domain utilizes distinct sets of amino acid residues to interact with FGFRs or TRKs in a mutually exclusive manner. The FGFR1 peptide wraps around the beta sandwich structure of the PTB domain, and its binding is possibly regulated by conformational change of a unique C-terminal beta strand in the protein. Our results suggest mechanisms by which SNTs serve as molecular switches to mediate the essential interplay between FGFR and TRK signaling during neuronal differentiation.
Insights
SNT adaptor proteins act as molecular switches, using distinct binding mechanisms for fibroblast growth factor receptors (FGFRs) and neurotrophin receptors (TRKs). This research reveals how SNTs mediate crucial FGFR and TRK signaling interplay in neuronal development.
Area of Science:
- Molecular Biology
- Cell Signaling
- Neuroscience
Background:
- SNT adaptor proteins link fibroblast growth factor receptor (FGFR) and neurotrophin receptor (TRK) signaling pathways to common downstream targets.
- The SNT-1 phosphotyrosine-binding (PTB) domain typically binds activated TRKs via an NPXpY motif but unusually interacts with non-phosphorylated FGFRs.
Purpose of the Study:
- To elucidate the distinct molecular mechanisms by which the SNT-1 PTB domain interacts with FGFRs and TRKs.
- To understand how these differential interactions enable SNT proteins to function as molecular switches in neuronal signaling.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy to analyze protein-ligand interactions.
- Site-directed mutagenesis to probe the roles of specific amino acid residues in binding.
- Peptide binding assays using FGFR1 and TRK-derived peptides.
Main Results:
- The SNT-1 PTB domain employs mutually exclusive sets of amino acid residues for binding FGFRs and TRKs.
- FGFR1 peptide binding involves a unique interaction with the PTB domain's beta sandwich structure.
- Binding to FGFRs may be regulated by conformational changes in a C-terminal beta strand of the PTB domain.
Conclusions:
- SNT adaptor proteins utilize distinct binding strategies for FGFRs and TRKs, highlighting their role as versatile signaling integrators.
- These findings provide insight into the molecular basis of how SNTs mediate the interplay between FGFR and TRK signaling pathways during neuronal differentiation.