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Diversity of Structural, Dynamic, and Environmental Effects Explain a Distinctive Functional Role of Transmembrane Domains in the Insulin Receptor Subfamily.

Authors :
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
Bocharov EV
Source :
International journal of molecular sciences [Int J Mol Sci] 2023 Feb 15; Vol. 24 (4). Date of Electronic Publication: 2023 Feb 15.
Publication Year :
2023

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.

Details

Language :
English
ISSN :
1422-0067
Volume :
24
Issue :
4
Database :
MEDLINE
Journal :
International journal of molecular sciences
Publication Type :
Academic Journal
Accession number :
36835322
Full Text :
https://doi.org/10.3390/ijms24043906