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Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes.
- Source :
- Cell Discovery; 6/28/2022, Vol. 8 Issue 1, p1-19, 19p
- Publication Year :
- 2022
-
Abstract
- As a critical node for insulin/IGF signaling, insulin receptor substrate 1 (IRS-1) is essential for metabolic regulation. A long and unstructured C-terminal region of IRS-1 recruits downstream effectors for promoting insulin/IGF signals. However, the underlying molecular basis for this remains elusive. Here, we found that the C-terminus of IRS-1 undergoes liquid-liquid phase separation (LLPS). Both electrostatic and hydrophobic interactions were seen to drive IRS-1 LLPS. Self-association of IRS-1, which was mainly mediated by the 301–600 region, drives IRS-1 LLPS to form insulin/IGF-1 signalosomes. Moreover, tyrosine residues of YXXM motifs, which recruit downstream effectors, also contributed to IRS-1 self-association and LLPS. Impairment of IRS-1 LLPS attenuated its positive effects on insulin/IGF-1 signaling. The metabolic disease-associated G972R mutation impaired the self-association and LLPS of IRS-1. Our findings delineate a mechanism in which LLPS of IRS-1-mediated signalosomes serves as an organizing center for insulin/IGF-1 signaling and implicate the role of aberrant IRS-1 LLPS in metabolic diseases. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 20565968
- Volume :
- 8
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Cell Discovery
- Publication Type :
- Academic Journal
- Accession number :
- 157686889
- Full Text :
- https://doi.org/10.1038/s41421-022-00426-x