6DU3

Structure of Scp1 D96N bound to REST-pS861/4 peptide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.58 Å

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Phosphatase activity of small C-terminal domain phosphatase 1 (SCP1) controls the stability of the key neuronal regulator RE1-silencing transcription factor (REST).

Burkholder, N.T.Mayfield, J.E.Yu, X.Irani, S.Arce, D.K.Jiang, F.Matthews, W.L.Xue, Y.Zhang, Y.J.

(2018) J Biol Chem 293: 16851-16861

  • DOI: https://doi.org/10.1074/jbc.RA118.004722
  • Primary Citation of Related Structures:  
    6DU2, 6DU3

  • PubMed Abstract: 

    The RE1-silencing transcription factor (REST) is the major scaffold protein for assembly of neuronal gene silencing complexes that suppress gene transcription through regulating the surrounding chromatin structure. REST represses neuronal gene expression in stem cells and non-neuronal cells, but it is minimally expressed in neuronal cells to ensure proper neuronal development. Dysregulation of REST function has been implicated in several cancers and neurological diseases. Modulating REST gene silencing is challenging because cellular and developmental differences can affect its activity. We therefore considered the possibility of modulating REST activity through its regulatory proteins. The human small C-terminal domain phosphatase 1 (SCP1) regulates the phosphorylation state of REST at sites that function as REST degradation checkpoints. Using kinetic analysis and direct visualization with X-ray crystallography, we show that SCP1 dephosphorylates two degron phosphosites of REST with a clear preference for phosphoserine 861 (pSer-861). Furthermore, we show that SCP1 stabilizes REST protein levels, which sustains REST's gene silencing function in HEK293 cells. In summary, our findings strongly suggest that REST is a bona fide substrate for SCP1 in vivo and that SCP1 phosphatase activity protects REST against degradation. These observations indicate that targeting REST via its regulatory protein SCP1 can modulate its activity and alter signaling in this essential developmental pathway.


  • Organizational Affiliation

    From the Departments of Molecular Biosciences and.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 1
A, B
180Homo sapiensMutation(s): 1 
Gene Names: CTDSP1NIF3NLIIFSCP1
EC: 3.1.3.16
UniProt & NIH Common Fund Data Resources
Find proteins for Q9GZU7 (Homo sapiens)
Explore Q9GZU7 
Go to UniProtKB:  Q9GZU7
PHAROS:  Q9GZU7
GTEx:  ENSG00000144579 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9GZU7
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
REST-pS861
C, D
12Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q13127 (Homo sapiens)
Explore Q13127 
Go to UniProtKB:  Q13127
PHAROS:  Q13127
GTEx:  ENSG00000084093 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13127
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
C, D
L-PEPTIDE LINKINGC3 H8 N O6 PSER
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.58 Å
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 125.414α = 90
b = 78.731β = 112.42
c = 63.001γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
SCALEPACKdata scaling
PHASERphasing
PDB_EXTRACTdata extraction
HKL-2000data reduction

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United States1R01GM104896-01A1
Robert A. Welch FoundationUnited StatesF-1778

Revision History  (Full details and data files)

  • Version 1.0: 2018-09-26
    Type: Initial release
  • Version 1.1: 2018-11-07
    Changes: Data collection, Database references
  • Version 1.2: 2020-01-01
    Changes: Author supporting evidence