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- Title
Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes.
- Authors
Gao, Xiu Kui; Rao, Xi Sheng; Cong, Xiao Xia; Sheng, Zu Kang; Sun, Yu Ting; Xu, Shui Bo; Wang, Jian Feng; Liang, Yong Heng; Lu, Lin Rong; Ouyang, Hongwei; Ge, Huiqing; Guo, Jian-sheng; Wu, Hang-jun; Sun, Qi Ming; Wu, Hao-bo; Bao, Zhang; Zheng, Li Ling; Zhou, Yi Ting
- 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.
- Subjects
INSULIN receptors; PHASE separation; METABOLIC regulation; HYDROPHOBIC interactions; ELECTROSTATIC interaction; METABOLIC disorders
- Publication
Cell Discovery, 2022, Vol 8, Issue 1, p1
- ISSN
2056-5968
- Publication type
Article
- DOI
10.1038/s41421-022-00426-x