6qzs
14-3-3 sigma in complex with FOXO1 pS256 peptide
Structural highlights
Function1433S_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). p53-regulated inhibitor of G2/M progression. Publication Abstract from PubMedForkhead 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 post-translational modifications. In response to growth factors, the Serine/Threonine kinase AKT phosphorylates T24 and S256 in FOXO1 to stimulate binding of 14-3-3 proteins thereby causing FOXO1 inactivation. In contrast, low nutrients and energy levels induce FOXO1 activity. AMPK-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis, partly mediates this effect through phosphorylation of S383 and T649 in FOXO1. In this study, we identified S22 as an additional AMPK phosphorylation site in FOXO1's N-terminus with S22 phosphorylation preventing binding of 14-3-3 proteins. The crystal structure of a FOXO1 peptide in complex with 14-3-3 sigma at 2.3 A resolution revealed that this is a consequence of both steric hindrance and electrostatic repulsion. Furthermore, we found that AMPK-mediated S22 phosphorylation impairs T24 phosphorylation by AKT in a hierarchical manner. Thus, numerous mechanisms maintain FOXO1 activity via AMPK signaling: AMPK-mediated S22 phosphorylation directly and indirectly averts binding of 14-3-3 proteins, whereas phosphorylation of S383 and T649 complementary 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. AMPK and AKT protein kinases hierarchically phosphorylate the N-terminus of the FOXO1 transcription factor, modulating interactions with 14-3-3 proteins.,Saline M, Badertscher L, Wolter M, Lau R, Gunnarsson A, Jacso T, Norris T, Ottmann C, Snijder A J Biol Chem. 2019 Jul 15. pii: RA119.008649. doi: 10.1074/jbc.RA119.008649. PMID:31308176[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
