Dataset Information

Trk Receptors and Neurotrophin Cross-Interactions: New Perspectives Toward Manipulating Therapeutic Side-Effects.

ABSTRACT: Some therapeutic side-effects result from simultaneous activation of homolog receptors by the same ligand. Tropomyosin receptor kinases (TrkA, TrkB and TrkC) play a major role in the development and biology of neurons through neurotrophin signaling. The wide range of cross-interactions between Trk receptors and neurotrophins vary in selectivity, affinity and function. In this study, we discuss new perspectives to the manipulation of side-effects via a better understanding of the cross-interactions at the molecular level, derived by computational methods. Available crystal structures of Trk receptors and neurotrophins are a valuable resource for exploitation via molecular mechanics (MM) and dynamics (MD). The study of the energetics and dynamics of neurotrophins or neurotrophic peptides interacting with Trk receptors will provide insight to structural regions that may be candidates for drug targeting and signaling pathway selection.

SUBMITTER: Haddad Y

PROVIDER: S-EPMC5414483 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Trk Receptors and Neurotrophin Cross-Interactions: New Perspectives Toward Manipulating Therapeutic Side-Effects.

Haddad Yazan Y Adam Vojtěch V Heger Zbyněk Z

Frontiers in molecular neuroscience 20170503

Some therapeutic side-effects result from simultaneous activation of homolog receptors by the same ligand. Tropomyosin receptor kinases (TrkA, TrkB and TrkC) play a major role in the development and biology of neurons through neurotrophin signaling. The wide range of cross-interactions between Trk receptors and neurotrophins vary in selectivity, affinity and function. In this study, we discuss new perspectives to the manipulation of side-effects via a better understanding of the cross-interactio ...[more]

PMID: 28515680

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Project description:Neurotrophism, structural plasticity, learning and long-term memory in mammals critically depend on neurotrophins binding Trk receptors to activate tyrosine kinase (TyrK) signaling, but Drosophila lacks full-length Trks, raising the question of how these processes occur in the fly. Paradoxically, truncated Trk isoforms lacking the TyrK predominate in the adult human brain, but whether they have neuronal functions independently of full-length Trks is unknown. Drosophila has TyrK-less Trk-family receptors, encoded by the kekkon (kek) genes, suggesting that evolutionarily conserved functions for this receptor class may exist. Here, we asked whether Keks function together with Drosophila neurotrophins (DNTs) at the larval glutamatergic neuromuscular junction (NMJ). We tested the eleven LRR and Ig-containing (LIG) proteins encoded in the Drosophila genome for expression in the central nervous system (CNS) and potential interaction with DNTs. Kek-6 is expressed in the CNS, interacts genetically with DNTs and can bind DNT2 in signaling assays and co-immunoprecipitations. Ligand binding is promiscuous, as Kek-6 can also bind DNT1, and Kek-2 and Kek-5 can also bind DNT2. In vivo, Kek-6 is found presynaptically in motoneurons, and DNT2 is produced by the muscle to function as a retrograde factor at the NMJ. Kek-6 and DNT2 regulate NMJ growth and synaptic structure. Evidence indicates that Kek-6 does not antagonise the alternative DNT2 receptor Toll-6. Instead, Kek-6 and Toll-6 interact physically, and together regulate structural synaptic plasticity and homeostasis. Using pull-down assays, we identified and validated CaMKII and VAP33A as intracellular partners of Kek-6, and show that they regulate NMJ growth and active zone formation downstream of DNT2 and Kek-6. The synaptic functions of Kek-6 could be evolutionarily conserved. This raises the intriguing possibility that a novel mechanism of structural synaptic plasticity involving truncated Trk-family receptors independently of TyrK signaling may also operate in the human brain.

Dataset Information

Trk Receptors and Neurotrophin Cross-Interactions: New Perspectives Toward Manipulating Therapeutic Side-Effects.

Publications

Trk Receptors and Neurotrophin Cross-Interactions: New Perspectives Toward Manipulating Therapeutic Side-Effects.

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