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

Journal Article · Mon May 06 04:00:00 EDT 2013 · Nature Structural & Molecular Biology

DOI:https://doi.org/10.1038/nsmb.2505· OSTI ID:1073519

Patrick, Aaron N.; Cabrera, Joshua H.; Smith, Anna L.; Chen, Xiaojiang S.; Ford, Heide L.; Zhao, Rui ^[1]

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1. USC

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: OTHERDODNIHOTHER U.S. STATESNCI
• OSTI ID: 1073519
• Journal Information: Nature Structural & Molecular Biology, Journal Name: Nature Structural & Molecular Biology Journal Issue: 4 Vol. 20; ISSN 1545-9993
• Publisher: Nature Publishing Group
• Country of Publication: United States
• Language: ENGLISH