5IC6

Crystal structure of caspase-7 DEVE peptide complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.200 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Cacidases: caspases can cleave after aspartate, glutamate and phosphoserine residues.

Seaman, J.E.Julien, O.Lee, P.S.Rettenmaier, T.J.Thomsen, N.D.Wells, J.A.

(2016) Cell Death Differ 23: 1717-1726

  • DOI: https://doi.org/10.1038/cdd.2016.62
  • Primary Citation of Related Structures:  
    5IC4, 5IC6

  • PubMed Abstract: 

    Caspases are a family of proteases found in all metazoans, including a dozen in humans, that drive the terminal stages of apoptosis as well as other cellular remodeling and inflammatory events. Caspases are named because they are cysteine class enzymes shown to cleave after aspartate residues. In the past decade, we and others have developed unbiased proteomic methods that collectively identified ~2000 native proteins cleaved during apoptosis after the signature aspartate residues. Here, we explore non-aspartate cleavage events and identify 100s of substrates cleaved after glutamate in both human and murine apoptotic samples. The extended consensus sequence patterns are virtually identical for the aspartate and glutamate cleavage sites suggesting they are cleaved by the same caspases. Detailed kinetic analyses of the dominant apoptotic executioner caspases-3 and -7 show that synthetic substrates containing DEVD↓ are cleaved only twofold faster than DEVE↓, which is well within the 500-fold range of rates that natural proteins are cut. X-ray crystallography studies confirm that the two acidic substrates bind in virtually the same way to either caspases-3 or -7 with minimal adjustments to accommodate the larger glutamate. Lastly, during apoptosis we found 121 proteins cleaved after serine residues that have been previously annotated to be phosphorylation sites. We found that caspase-3, but not caspase-7, can cleave peptides containing DEVpS↓ at only threefold slower rate than DEVD↓, but does not cleave the unphosphorylated serine peptide. There are only a handful of previously reported examples of proteins cleaved after glutamate and none after phosphorserine. Our studies reveal a much greater promiscuity for cleaving after acidic residues and the name 'cacidase' could aptly reflect this broader specificity.


  • Organizational Affiliation

    Department of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Caspase-7 subunit p20
A, C
198Homo sapiensMutation(s): 0 
Gene Names: CASP7MCH3
EC: 3.4.22.60
UniProt & NIH Common Fund Data Resources
Find proteins for P55210 (Homo sapiens)
Explore P55210 
Go to UniProtKB:  P55210
PHAROS:  P55210
GTEx:  ENSG00000165806 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP55210
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Caspase-7 subunit p11
B, D
113Homo sapiensMutation(s): 0 
Gene Names: CASP7MCH3
EC: 3.4.22.60
UniProt & NIH Common Fund Data Resources
Find proteins for P55210 (Homo sapiens)
Explore P55210 
Go to UniProtKB:  P55210
PHAROS:  P55210
GTEx:  ENSG00000165806 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP55210
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
DEVE peptide
E, F
4synthetic constructMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.200 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.142α = 90
b = 88.501β = 90
c = 103.383γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-07-20
    Type: Initial release
  • Version 1.1: 2016-10-05
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.3: 2023-11-15
    Changes: Data collection, Derived calculations