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The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction.
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- Author(s): Woo JR;Woo JR; Bae SH; Bae SH; Bae SH; Wales TE; Wales TE; Engen JR; Engen JR; Lee J; Lee J; Jang H; Jang H; Jang H; Park S; Park S; Park S
- Source:
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Apr 23; Vol. 121 (17), pp. e2401716121. Date of Electronic Publication: 2024 Apr 16.- Publication Type:
Journal Article- Language:
English - Source:
- Additional Information
- Source: Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
- Publication Information: Original Publication: Washington, DC : National Academy of Sciences
- Subject Terms: Insulin Resistance* ; Diabetes Mellitus, Type 2*; Mice ; Humans ; Animals ; Phosphorylation ; Serine/metabolism ; Receptor, Insulin/metabolism ; Insulin Receptor Substrate Proteins/genetics ; Insulin Receptor Substrate Proteins/metabolism ; Cell Line ; Phosphoproteins/metabolism ; Insulin/metabolism
- Abstract: 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.
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J Biol Chem. 2007 Jun 22;282(25):18018-18027. (PMID: 17446166) - Grant Information: RS-2023-00243435 National Research Foundation of Korea (NRF); 2021R1A6A1A10044154 National Research Foundation of Korea (NRF)
- Contributed Indexing: Keywords: IRS-1; diabetes; insulin receptor; insulin resistance; serine phosphorylation
- Accession Number: 452VLY9402 (Serine)
EC 2.7.10.1 (Receptor, Insulin)
0 (Insulin Receptor Substrate Proteins)
0 (Phosphoproteins)
0 (Insulin) - Publication Date: Date Created: 20240416 Date Completed: 20240418 Latest Revision: 20240428
- Publication Date: 20240428
- Accession Number: PMC11046688
- Accession Number: 10.1073/pnas.2401716121
- Accession Number: 38625937
- Source:
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