Diversity of Structural, Dynamic, and Environmental Effects Explain a Distinctive Functional Role of Transmembrane Domains in the Insulin Receptor Subfamily.
Int J Mol Sci
; 24(4)2023 Feb 15.
Article
in En
| MEDLINE
| ID: mdl-36835322
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptor, Insulin
/
Drug Development
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Int J Mol Sci
Year:
2023
Document type:
Article
Affiliation country:
Rusia