6BNT

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

6BNT の概要

• エントリーDOI: 10.2210/pdb6bnt/pdb
• 分子名称: AP-2 complex subunit mu, Insulin receptor substrate 1 (3 entities in total)
• 機能のキーワード: ap2 mu1, irs1, endocytosis
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 37359.33

構造登録者

Kikuchi, S.,Choi, E.,Yu, H. (登録日: 2017-11-17, 公開日: 2018-11-21, 最終更新日: 2024-10-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.2 Å)