Structure-function analyses of the human SIX1–EYA2 complex reveal insights into metastasis and BOR syndrome
Copyright policy )Structure-function analyses of the human SIX1–EYA2 complex reveal insights into metastasis and BOR syndrome
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.
- University of Colorado Anschutz Medical Campus United States
- University of Southern California United States
- University of California System United States
Homeodomain Proteins, Models, Molecular, Intracellular Signaling Peptides and Proteins, Mutation, Missense, Mice, Nude, Nuclear Proteins, Article, Mice, Structure-Activity Relationship, MCF-7 Cells, Animals, Humans, Neoplasm Metastasis, Protein Tyrosine Phosphatases, Branchio-Oto-Renal Syndrome
Homeodomain Proteins, Models, Molecular, Intracellular Signaling Peptides and Proteins, Mutation, Missense, Mice, Nude, Nuclear Proteins, Article, Mice, Structure-Activity Relationship, MCF-7 Cells, Animals, Humans, Neoplasm Metastasis, Protein Tyrosine Phosphatases, Branchio-Oto-Renal Syndrome
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