1. Diversity of Structural, Dynamic, and Environmental Effects Explain a Distinctive Functional Role of Transmembrane Domains in the Insulin Receptor Subfamily.
- Author
-
Bershatsky YV, Kuznetsov AS, Idiatullina AR, Bocharova OV, Dolotova SM, Gavrilenkova AA, Serova OV, Deyev IE, Rakitina TV, Zangieva OT, Pavlov KV, Batishchev OV, Britikov VV, Usanov SA, Arseniev AS, Efremov RG, and Bocharov EV
- Subjects
- Humans, Protein Domains, Signal Transduction, Receptor, Insulin chemistry, Receptor, Insulin physiology, Drug Development
- Abstract
Human InsR, IGF1R, and IRR receptor tyrosine kinases (RTK) of the insulin receptor subfamily play an important role in signaling pathways for a wide range of physiological processes and are directly associated with many pathologies, including neurodegenerative diseases. The disulfide-linked dimeric structure of these receptors is unique among RTKs. Sharing high sequence and structure homology, the receptors differ dramatically in their localization, expression, and functions. In this work, using high-resolution NMR spectroscopy supported by atomistic computer modeling, conformational variability of the transmembrane domains and their interactions with surrounding lipids were found to differ significantly between representatives of the subfamily. Therefore, we suggest that the heterogeneous and highly dynamic membrane environment should be taken into account in the observed diversity of the structural/dynamic organization and mechanisms of activation of InsR, IGF1R, and IRR receptors. This membrane-mediated control of receptor signaling offers an attractive prospect for the development of new targeted therapies for diseases associated with dysfunction of insulin subfamily receptors.
- Published
- 2023
- Full Text
- View/download PDF