Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 20, Issue 4, Pages 447-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2505
Keywords
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Funding
- NCI NIH HHS [P30 CA046934, P30CA046934, 2R01-CA095277, R01 CA157790, R01 CA095277, T32 CA082086, R01CA157790] Funding Source: Medline
- NIDA NIH HHS [R03 DA033174, R03DA030559, R03 DA030559, R03DA033174] Funding Source: Medline
- PHS HHS [2T32082086-11A1] Funding Source: Medline
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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-angstrom 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.
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