4CI8

Crystal structure of the tandem atypical beta-propeller domain of EML1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Crystal Structure of Eml1 Reveals the Basis for Hsp90 Dependence of Oncogenic Eml4-Alk by Disruption of an Atypical Beta-Propeller Domain.

Richards, M.W.Law, E.W.P.Rennalls, L.P.Busacca, S.O'Regan, L.Fry, A.M.Fennell, D.A.Bayliss, R.

(2014) Proc Natl Acad Sci U S A 111: 5195

  • DOI: https://doi.org/10.1073/pnas.1322892111
  • Primary Citation of Related Structures:  
    4CI8

  • PubMed Abstract: 

    Proteins of the echinoderm microtubule-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase microtubule network. They contain a unique hydrophobic EML protein (HELP) motif and a variable number of WD40 repeats. Recurrent gene rearrangements in nonsmall cell lung cancer fuse EML4 to anaplastic lymphoma kinase (ALK), causing expression of several fusion oncoprotein variants. We have determined a 2.6-Å crystal structure of the representative ∼70-kDa core of EML1, revealing an intimately associated pair of β-propellers, which we term a TAPE (tandem atypical propeller in EMLs) domain. One propeller is highly atypical, having a discontinuous subdomain unrelated to a WD40 motif in place of one of its blades. This unexpected feature shows how a propeller structure can be assembled from subdomains with distinct folds. The HELP motif is not an independent domain but forms part of the hydrophobic core that joins the two β-propellers. The TAPE domain binds α/β-tubulin via its conserved, concave surface, including part of the atypical blade. Mapping the characteristic breakpoints of each EML4-ALK variant onto our structure indicates that the EML4 TAPE domain is truncated in many variants in a manner likely to make the fusion protein structurally unstable. We found that the heat shock protein 90 (Hsp90) inhibitor ganetespib induced degradation of these variants whereas others lacking a partial TAPE domain were resistant in both overexpression models and patient-derived cell lines. The Hsp90-sensitive EML4-ALK variants are exceptions to the rule that oncogenic fusion proteins involve breakpoints in disordered regions of both partners.


  • Organizational Affiliation

    Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ECHINODERM MICROTUBULE-ASSOCIATED PROTEIN-LIKE 1
A, B
655Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for O00423 (Homo sapiens)
Explore O00423 
Go to UniProtKB:  O00423
PHAROS:  O00423
GTEx:  ENSG00000066629 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO00423
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SO4
Query on SO4

Download Ideal Coordinates CCD File 
AA [auth B]
C [auth A]
D [auth A]
E [auth A]
F [auth A]
AA [auth B],
C [auth A],
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth B],
Q [auth B],
R [auth B],
S [auth B],
T [auth B],
U [auth B],
V [auth B],
W [auth B],
X [auth B],
Y [auth B],
Z [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.98α = 90
b = 83.98β = 96.61
c = 115.52γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-04-16
    Type: Initial release
  • Version 1.1: 2017-07-12
    Changes: Refinement description