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Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome.

Abstract
SIX1 interacts with EYA to form a bipartite transcription factor essential for mammalian development. Loss of function of this complex causes branchio-oto-renal (BOR) syndrome, whereas re-expression of SIX1 or EYA promotes metastasis. Here we describe the 2.0-Å structure of SIX1 bound to EYA2, which suggests a new DNA-binding mechanism for SIX1 and provides a rationale for the effect of BOR syndrome mutations. The structure also reveals that SIX1 uses predominantly a single helix to interact with EYA. Substitution of a single amino acid in this helix is sufficient to disrupt SIX1-EYA interaction, SIX1-mediated epithelial-mesenchymal transition and metastasis in mouse models. Given that SIX1 and EYA are overexpressed in many tumor types, our data indicate that targeting the SIX1-EYA complex may be a potent approach to inhibit tumor progression in multiple cancer types.
AuthorsAaron N Patrick, Joshua H Cabrera, Anna L Smith, Xiaojiang S Chen, Heide L Ford, Rui Zhao
JournalNature structural & molecular biology (Nat Struct Mol Biol) Vol. 20 Issue 4 Pg. 447-53 (Apr 2013) ISSN: 1545-9985 [Electronic] United States
PMID23435380 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • SIX1 protein, human
  • EYA2 protein, human
  • Protein Tyrosine Phosphatases
Topics
  • Animals
  • Branchio-Oto-Renal Syndrome (genetics, physiopathology)
  • Homeodomain Proteins (chemistry, physiology)
  • Humans
  • Intracellular Signaling Peptides and Proteins (chemistry, physiology)
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Mutation, Missense
  • Neoplasm Metastasis (physiopathology)
  • Nuclear Proteins (chemistry, physiology)
  • Protein Tyrosine Phosphatases (chemistry, physiology)
  • Structure-Activity Relationship

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