The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction

• 成果类型: Article
• 署名作者: Woo, Ju Rang; Bae, Seung-Hyun; Wales, Thomas E.; Engen, John R.; Lee, Jongsoon; Jang, Hyonchol; Park, Sangyoun
• 署名单位: National Cancer Center - Korea (NCC); National Cancer Center - Korea (NCC); Northeastern University; Soonchunhyang University; Soongsil University; Soongsil University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9124
• DOI: 10.1073/pnas.2401716121
• 发表日期: 2024-04-23
• 关键词: insulin-receptor substrate-1; endoplasmic-reticulum stress; tyrosine-phosphatase 1b; crystal-structure; skeletal-muscle; resistance; obesity; kinase; sensitivity; shc

摘要

Serine phosphorylations on insulin receptor substrate 1 (IRS - 1) by diverse kinases aoccur widely during obesity - , stress - , and inflammation - induced conditions in models of insulin resistance and type 2 diabetes. In this study, we define a region within the human IRS - 1, which is directly C - terminal to the PTB domain encompassing numerous serine phosphorylation sites including Ser307 (mouse Ser302) and Ser312 (mouse 307) creating a phosphorylation insulin resistance (PIR) domain. We demonstrate that the IRS - 1 PTB - PIR with its unphosphorylated serine residues interacts with the insulin receptor (IR) but loses the IR - binding when they are phosphorylated. Surface plasmon resonance studies further confirm that the PTB - PIR binds stronger to IR than just the PTB domain, and that phosphorylations at Ser307, Ser312, Ser315, and Ser323 within the PIR domain result in abrogating the binding. Insulin - responsive cells containing the mutant IRS - 1 with all these four serines changed into glutamates to mimic phosphorylations show decreased levels of phosphorylations in IR, IRS - 1, and AKT compared to the wild - type IRS - 1. Hydrogen-deuterium exchange mass spectrometry experiments indicating the PIR domain interacting with the N - terminal lobe and the hinge regions of the IR kinase domain further suggest the possibility that the IRS - 1 PIR domain protects the IR from the PTP1B - mediated dephosphorylation.