6QZR

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.223 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

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.

(2019) J Biol Chem 294: 13106-13116

  • DOI: https://doi.org/10.1074/jbc.RA119.008649
  • Primary Citation of Related Structures:  
    6QZR, 6QZS

  • 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 24 and Ser 256 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 383 and Thr 649 in FOXO1. In this study, we identified Ser 22 as an additional AMPK phosphorylation site in FOXO1's N terminus, with Ser 22 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 22 phosphorylation impairs Thr 24 phosphorylation by AKT in a hierarchical manner. Thus, numerous mechanisms maintain FOXO1 activity via AMPK signaling. AMPK-mediated Ser 22 phosphorylation directly and indirectly averts binding of 14-3-3 proteins, whereas phosphorylation of Ser 383 and Thr 649 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.


  • Organizational Affiliation

    Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
14-3-3 protein sigma253Homo sapiensMutation(s): 0 
Gene Names: SFNHME1
UniProt & NIH Common Fund Data Resources
Find proteins for P31947 (Homo sapiens)
Explore P31947 
Go to UniProtKB:  P31947
PHAROS:  P31947
GTEx:  ENSG00000175793 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP31947
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Forkhead box protein O111Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q12778 (Homo sapiens)
Explore Q12778 
Go to UniProtKB:  Q12778
PHAROS:  Q12778
GTEx:  ENSG00000150907 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ12778
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
B3P
Query on B3P

Download Ideal Coordinates CCD File 
Q [auth A],
T [auth B],
W [auth F],
X [auth H]
2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL
C11 H26 N2 O6
HHKZCCWKTZRCCL-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
AA [auth G]
R [auth A]
S [auth A]
U [auth D]
V [auth D]
AA [auth G],
R [auth A],
S [auth A],
U [auth D],
V [auth D],
Y [auth H],
Z [auth H]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
CSO
Query on CSO
A
B
C
D
E
A,
B,
C,
D,
E,
F,
G [auth H],
H [auth G]
L-PEPTIDE LINKINGC3 H7 N O3 SCYS
TPO
Query on TPO
I [auth R]
J
K [auth M]
L [auth N]
M [auth O]
I [auth R],
J,
K [auth M],
L [auth N],
M [auth O],
N [auth P],
O [auth T],
P [auth U]
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.223 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 149.205α = 90
b = 62.806β = 103.24
c = 154.044γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DIALSdata reduction
Aimlessdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European CommissionNetherlands--

Revision History  (Full details and data files)

  • Version 1.0: 2019-07-31
    Type: Initial release
  • Version 1.1: 2019-09-11
    Changes: Data collection, Database references
  • Version 1.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description