6QZR

14-3-3 sigma in complex with FOXO1 pT24 peptide

6QZR の概要

• エントリーDOI: 10.2210/pdb6qzr/pdb
• 関連するPDBエントリー: 6qzs
• 分子名称: 14-3-3 protein sigma, Forkhead box protein O1, 2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (5 entities in total)
• 機能のキーワード: protein binding, 14-3-3, foxo1, peptide binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 16
• 化学式量合計: 239199.04

構造登録者

Ottmann, C.,Wolter, M.,Lau, R.A. (登録日: 2019-03-12, 公開日: 2019-07-31, 最終更新日: 2024-10-23)

主引用文献

Saline, M.,Badertscher, L.,Wolter, M.,Lau, R.,Gunnarsson, A.,Jacso, T.,Norris, T.,Ottmann, C.,Snijder, A.
AMPK and AKT protein kinases hierarchically phosphorylate the N-terminus of the FOXO1 transcription factor, modulating interactions with 14-3-3 proteins.
J.Biol.Chem., 294:13106-13116, 2019

PubMed Abstract: Forkhead box protein O1 (FOXO1) is a transcription factor involved in various cellular processes such as glucose metabolism, development, stress resistance, and tumor suppression. FOXO1's transcriptional activity is controlled by different environmental cues through a myriad of posttranslational modifications. In response to growth factors, the serine/threonine kinase AKT phosphorylates Thr and Ser in FOXO1 to stimulate binding of 14-3-3 proteins, causing FOXO1 inactivation. In contrast, low nutrient and energy levels induce FOXO1 activity. AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis, partly mediates this effect through phosphorylation of Ser and Thr in FOXO1. In this study, we identified Ser as an additional AMPK phosphorylation site in FOXO1's N terminus, with Ser phosphorylation preventing binding of 14-3-3 proteins. The crystal structure of a FOXO1 peptide in complex with 14-3-3 σ at 2.3 Å resolution revealed that this is a consequence of both steric hindrance and electrostatic repulsion. Furthermore, we found that AMPK-mediated Ser phosphorylation impairs Thr phosphorylation by AKT in a hierarchical manner. Thus, numerous mechanisms maintain FOXO1 activity via AMPK signaling. AMPK-mediated Ser phosphorylation directly and indirectly averts binding of 14-3-3 proteins, whereas phosphorylation of Ser and Thr complementarily stimulates FOXO1 activity. Our results shed light on a mechanism that integrates inputs from both AMPK and AKT signaling pathways in a small motif to fine-tune FOXO1 transcriptional activity.

PubMed: 31308176
DOI: 10.1074/jbc.RA119.008649

実験手法

X-RAY DIFFRACTION (2.3 Å)