5V4B

Crystal structure of the Skp1-FBXW7-DISC1 complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.185 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system.

Yalla, K.Elliott, C.Day, J.P.Findlay, J.Barratt, S.Hughes, Z.A.Wilson, L.Whiteley, E.Popiolek, M.Li, Y.Dunlop, J.Killick, R.Adams, D.R.Brandon, N.J.Houslay, M.D.Hao, B.Baillie, G.S.

(2018) Mol Psychiatry 23: 1278-1286

  • DOI: https://doi.org/10.1038/mp.2017.138
  • Primary Citation of Related Structures:  
    5V4B

  • PubMed Abstract: 

    Disrupted in schizophrenia 1 (DISC1) is a multi-functional scaffolding protein that has been associated with neuropsychiatric disease. The role of DISC1 is to assemble protein complexes that promote neural development and signaling, hence tight control of the concentration of cellular DISC1 in neurons is vital to brain function. Using structural and biochemical techniques, we show for we believe the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the F-Box protein, FBXW7. We present the structure of FBXW7 bound to the DISC1 phosphodegron motif and exploit this information to prove that disruption of the FBXW7-DISC1 complex results in a stabilization of DISC1. This action can counteract DISC1 deficiencies observed in neural progenitor cells derived from induced pluripotent stem cells from schizophrenia patients with a DISC1 frameshift mutation. Thus manipulation of DISC1 levels via the UPS may provide a novel method to explore DISC1 function.


  • Organizational Affiliation

    College of Veterinary Medical and Life Sciences, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
S-phase kinase-associated protein 1,S-phase kinase-associated protein 1149Homo sapiensMutation(s): 1 
Gene Names: SKP1EMC19OCP2SKP1ATCEB1L
UniProt & NIH Common Fund Data Resources
Find proteins for P63208 (Homo sapiens)
Explore P63208 
Go to UniProtKB:  P63208
PHAROS:  P63208
GTEx:  ENSG00000113558 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP63208
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
F-box/WD repeat-containing protein 7444Homo sapiensMutation(s): 0 
Gene Names: FBXW7FBW7FBX30SEL10
UniProt & NIH Common Fund Data Resources
Find proteins for Q969H0 (Homo sapiens)
Explore Q969H0 
Go to UniProtKB:  Q969H0
PHAROS:  Q969H0
GTEx:  ENSG00000109670 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ969H0
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
DISC1 peptide15Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NRI5 (Homo sapiens)
Explore Q9NRI5 
Go to UniProtKB:  Q9NRI5
PHAROS:  Q9NRI5
GTEx:  ENSG00000162946 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9NRI5
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth B]
E [auth B]
F [auth B]
G [auth B]
H [auth B]
D [auth B],
E [auth B],
F [auth B],
G [auth B],
H [auth B],
I [auth B],
J [auth B],
K [auth B],
L [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
IMD
Query on IMD

Download Ideal Coordinates CCD File 
M [auth B]IMIDAZOLE
C3 H5 N2
RAXXELZNTBOGNW-UHFFFAOYSA-O
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
C
L-PEPTIDE LINKINGC3 H8 N O6 PSER
TPO
Query on TPO
C
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.185 
  • Space Group: I 41 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 233.514α = 90
b = 233.514β = 90
c = 108.438γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-09-20
    Type: Initial release
  • Version 1.1: 2018-05-16
    Changes: Data collection, Database references
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references, Refinement description