title: 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.
authors: Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: Aaron N
authors: AN
authors: Patrick
authors: Joshua H
authors: JH
authors: Cabrera
authors: Anna L
authors: AL
authors: Smith
authors: Xiaojiang S
authors: XS
authors: Chen
authors: Heide L
authors: HL
authors: Ford
authors: Rui
authors: R
authors: Zhao
mesh_terms: D000818:Animals; D019280:Branchio-Oto-Renal Syndrome / Q000235:genetics / Q000503:physiopathology*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000502:physiology*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D020125:Mutation, Missense; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C099236:SIX1 protein, human; C106938:EYA2 protein, human; D017027:Protein Tyrosine Phosphatases