![]() Both receptors can be activated by peptide hormones (insulin, IGF1, and IGF2) and are widely expressed in diverse tissues of the organism. Besides cell signaling, InsR plays a key role in the metabolism of lipids, proteins, and carbohydrates as well as in the maintenance of glucose homeostasis. IGF1R regulates cell growth, proliferation, and differentiation. Members of the insulin receptor subfamily share more than 70% sequence homology, however, they differ dramatically in terms of localization, expression, and functional roles. Abnormal functioning of the receptors has been associated with a wide range of human pathologies including diabetes, cancer, and neurodegenerative disorders such as Alzheimer’s disease. These proteins are involved in fundamental physiological processes such as growth, division, differentiation, and survival. The insulin receptor subfamily contains three highly homologous receptors: the insulin receptor (InsR), the insulin-like growth factor-1 receptor (IGF1R), and an orphan insulin receptor-related receptor (IRR). The human RTKs family contains 58 receptors divided into 20 subfamilies. Receptor tyrosine kinases (RTKs) are ubiquitous receptors in the human organism. 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. 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. 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. Sharing high sequence and structure homology, the receptors differ dramatically in their localization, expression, and functions. The disulfide-linked dimeric structure of these receptors is unique among RTKs. 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.
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