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

Author:

Woo Ju Rang1,Bae Seung-Hyun23ORCID,Wales Thomas E.4,Engen John R.4ORCID,Lee Jongsoon5ORCID,Jang Hyonchol23ORCID,Park SangYoun67

Affiliation:

1. Division of Convergence Technology, New Drug Development Center, KBIOHealth, Cheongju 28160, Republic of Korea

2. Division of Rare and Refractory Cancer, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea

3. Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang 10408, Republic of Korea

4. Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115

5. Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, Cheonan 31151, Republic of Korea

6. School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea

7. Integrative Institute of Basic Sciences, Soongsil University, Seoul 06978, Republic of Korea

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.

Funder

National Research Foundation of Korea

Publisher

Proceedings of the National Academy of Sciences

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