Structural insights into the specificity of adaptor proteins Dok5 and Dok6 Docking to Trk receptors

Area of Science:

• Molecular Biology
• Structural Biology
• Neuroscience

Background:

• Neurotrophic signaling by Trk receptors is crucial for neuronal function.
• Selective recruitment of downstream adaptors like Dok5 and Dok6 dictates signaling outcomes.
• The structural basis for Trk-Dok specificity remained unclear.

Purpose of the Study:

• To elucidate the structural principles governing Trk-Dok signaling specificity.
• To understand how Trk receptors differentiate between Dok5 and Dok6 adaptors.
• To provide insights into neurotrophin signaling for potential therapeutic targeting.

Main Methods:

• Utilized AlphaFold3 for structural prediction of Trk-Dok complexes.
• Performed biochemical validation including co-immunoprecipitation assays.
• Analyzed structural models to interpret pocket architectures and interaction hotspots.

Main Results:

• Structural models revealed distinct pocket architectures in Trk intracellular domains for Dok5 and Dok6.
• Phosphorylation of Trk tyrosine residues exposes docking sites for PTB domains.
• A conserved interaction hotspot involving Trk Tyr515/516 and Dok Tyr187 was identified.
• Dok C-terminal domains were shown to modulate interactions via steric hindrance.

Conclusions:

• Spatial complementarity and phosphorylation-dependent site exposure are key to Trk-Dok specificity.
• This study provides novel structural insights into neurotrophin signal transduction.
• Findings may inform therapeutic strategies targeting neurotrophin signaling pathways.