•연구자: 의생명시스템학부 박상연
•발표일: 2024.04.16
•DOI: https://doi.org/10.1073/pnas.2401716121
•Ju Rang Woo et al., PNAS (Q1); Volume 121, Issue 17, e2401716121 (2024)
•Abstract
Serine phosphorylations on insulin receptor substrate 1 (IRS- 1) by diverse kinases aoc-cur 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 phospho-rylations 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.