4egc
From Proteopedia
Crystal Structure of MBP-fused Human Six1 Bound to Human Eya2 Eya Domain
Structural highlights
Disease[SIX1_HUMAN] Autosomal dominant non-syndromic sensorineural deafness type DFNA;BOR syndrome;Branchiootic syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. Defects in SIX1 could be a cause of branchiootorenal syndrome (BOR). BOR is an autosomal dominant disorder manifested by various combinations of preauricular pits, branchial fistulae or cysts, lacrimal duct stenosis, hearing loss, structural defects of the outer, middle, or inner ear, and renal dysplasia. Associated defects include asthenic habitus, long narrow facies, constricted palate, deep overbite, and myopia. Hearing loss may be due to mondini type cochlear defect and stapes fixation. Penetrance of BOR syndrome is high, although expressivity can be extremely variable.[1] [2] Function[MALE_ECOLI] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.[SIX1_HUMAN] Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development (By similarity). Plays an important role in the development of several organs, including kidney, muscle and inner ear (By similarity). Depending on context, functions as transcriptional repressor or activator (By similarity). Lacks an activation domain, and requires interaction with EYA family members for transcription activation (PubMed:15141091). Mediates nuclear translocation of EYA1 and EYA2 (PubMed:19497856). Binds the 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 element in the MYOG promoter and CIDEA enhancer (PubMed:27923061, PubMed:23435380, PubMed:15141091, PubMed:19497856). Regulates the expression of numerous genes, including MYC, CCND1 and EZR (By similarity). Acts as activator of the IGFBP5 promoter, probably coactivated by EYA2 (By similarity). Repression of precursor cell proliferation in myoblasts is switched to activation through recruitment of EYA3 to the SIX1-DACH1 complex (By similarity). During myogenesis, seems to act together with EYA2 and DACH2 (By similarity). Regulates the expression of CCNA1 (PubMed:15123840). Promotes brown adipocyte differentiation (By similarity).[UniProtKB:Q62231][3] [4] [5] [6] [7] Publication Abstract from PubMedSIX1 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-A 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. Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome.,Patrick AN, Cabrera JH, Smith AL, Chen XS, Ford HL, Zhao R Nat Struct Mol Biol. 2013 Feb 24. doi: 10.1038/nsmb.2505. PMID:23435380[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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