Molecular determinants of signal transduction in tropomyosin receptor kinases

TL;DR

This paper reviews how Trk receptors use structural changes and ligand interactions to control diverse signaling outcomes in neurons.

Contribution

The paper introduces a focus on allosteric modulation and ligand bias as key mechanisms shaping Trk receptor signaling.

Findings

Allosteric modulation and ligand binding influence Trk receptor conformational changes.

Ligand bias allows different neurotrophins to selectively activate specific signaling pathways.

Structural insights into Trk receptors could improve drug design for neurological disorders.

Abstract

Tropomyosin receptor kinase (Trk) receptors are essential regulators of neuronal development, survival, and plasticity through their interactions with neurotrophins. This review examines the structural and molecular mechanisms connecting ligand binding to the diverse signaling outcomes of Trk receptors. We analyze how neurotrophin binding and allosteric interactions trigger conformational changes that activate distinct signaling pathways. Our discussion explores how allosteric modulation—binding of ligands to sites distinct from the primary receptor site—and ligand bias—where different neurotrophins binding the same receptor preferentially activate certain downstream pathways—may together shape receptor function, focusing on structural and conformational mechanisms. Despite recent advances, important structural details remain unresolved. Further insights into Trk receptor structure and dynamics could significantly enhance therapeutic development by enabling the design of drugs that selectively target‐specific signaling pathways.

Tropomyosin receptor kinases control critical neuronal functions, but how do the same receptors produce diverse cellular responses? This review explores the structural mechanisms behind Trk signaling diversity, focusing on allosteric modulation and ligand bias. Understanding how these mechanisms shape the conformational landscape of flexible receptor domains and thereby modulate signaling outcomes can offer new therapeutic opportunities for neurological disorders.

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