Biology subjects

Arseniev, A. S.

Publications and source records attributed to Arseniev, A. S..

3 recordsLinked to original sources

bioRxiv2023

Structural Basis for the transmembrane signaling and antidepressant-induced activation of the receptor tyrosine kinase TrkB

Neurotrophin receptors of the Trk family are involved in the regulation of brain development and neuroplasticity, and therefore can serve as targets for anti-cancer and stroke-recovery drugs, antidepressants, and many others. The structures of Trk protein domains in various states upon activation need to be elucidated to allow rational drug design. However, little is known about the conformations of the transmembrane and juxtamembrane domains of Trk receptors. In the present study, we employed NMR spectroscopy to solve the structure of the TrkB dimeric transmembrane domain in the lipid environment. We verified the structure using mutagenesis and confirmed that the conformation corresponds to the active state of the receptor. Subsequent study of TrkB interaction with the antidepressant drug fluoxetine, and the antipsychotic drug chlorpromazine, provided a clear self-consistent model, describing the mechanism by which fluoxetine activates the receptor by binding to its transmembrane domain.

biochemistry↗

bioRxiv2021

Neurotrophin signaling is modulated by specific transmembrane domain interactions

The neurotrophin receptors p75 and TrkA play an important role in the development and survival of the nervous system. Biochemical data suggest that p75 and TrkA regulate the activities of each other. For instance, p75 is able to regulate the response of TrkA to lower concentrations of NGF and TrkA promotes p75 shedding by -secretases in a ligand-dependent manner. The current model is that p75 and TrkA are regulated by means of a physical direct interaction, however the nature of such interaction has been elusive so far. Here using NMR in micelles, multiscale molecular dynamics (MD), FRET and functional studies we identified and characterized the direct interaction between TrkA and p75 through the transmembrane domains (TMDs). MD of p75-TMD mutants suggests that although the interaction between TrkA and p75 TMDs is maintained, a specific protein interface is required to facilitate TrkA active homodimerization in the presence of NGF. The same mutations in the TMD protein interface of p75 reduced the activation of TrkA by NGF and cell differentiation. In summary we provide a structural model of the p75/TrkA receptor complex stabilized by transmembrane domain interactions.

biochemistry↗

bioRxiv2020

NanoFAST: Structure-based design of a small fluorogen-activating protein with only 98 amino acids

One of the essential characteristics of any tag used in bioscience and medical applications is its size. The larger the label, the more it may affect the studied object, and the more it may distort its behavior. In this paper, using NMR spectroscopy and X-ray crystallography, we have studied the structure of fluorogen-activating protein FAST both in the apo form and in complex with the fluorogen. We shown that significant change in the protein occurs upon interaction with the ligand. While the protein is completely ordered in the complex, its apo form is characterized by higher mobility and disordering of its N-terminus. We used structural information to design the shortened FAST (which we named nanoFAST) by truncating 26 N-terminal residues. Thus, we created the shortest genetically encoded tag among all known fluorescent and fluorogen-activating proteins, which is composed of only 98 amino acids.

biochemistry↗