6BNT

Crystal structure of AP2 mu1 adaptin C-terminal domain with IRS-1 peptide

Summary for 6BNT

• Entry DOI: 10.2210/pdb6bnt/pdb
• Descriptor: AP-2 complex subunit mu, Insulin receptor substrate 1 (3 entities in total)
• Functional Keywords: ap2 mu1, irs1, endocytosis
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 37359.33

Authors

Kikuchi, S.,Choi, E.,Yu, H. (deposition date: 2017-11-17, release date: 2018-11-21, Last modification date: 2024-10-30)

Primary citation

Choi, E.,Kikuchi, S.,Gao, H.,Brodzik, K.,Nassour, I.,Yopp, A.,Singal, A.G.,Zhu, H.,Yu, H.
Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling.
Nat Commun, 10:1473-1473, 2019

PubMed Abstract: Insulin controls glucose homeostasis and cell growth through bifurcated signaling pathways. Dysregulation of insulin signaling is linked to diabetes and cancer. The spindle checkpoint controls the fidelity of chromosome segregation during mitosis. Here, we show that insulin receptor substrate 1 and 2 (IRS1/2) cooperate with spindle checkpoint proteins to promote insulin receptor (IR) endocytosis through recruiting the clathrin adaptor complex AP2 to IR. A phosphorylation switch of IRS1/2 orchestrated by extracellular signal-regulated kinase 1 and 2 (ERK1/2) and Src homology phosphatase 2 (SHP2) ensures selective internalization of activated IR. SHP2 inhibition blocks this feedback regulation and growth-promoting IR signaling, prolongs insulin action on metabolism, and improves insulin sensitivity in mice. We propose that mitotic regulators and SHP2 promote feedback inhibition of IR, thereby limiting the duration of insulin signaling. Targeting this feedback inhibition can improve insulin sensitivity.

PubMed: 30931927
DOI: 10.1038/s41467-019-09318-3

Experimental method

X-RAY DIFFRACTION (3.2 Å)