title: Structure of p73 DNA-binding domain tetramer modulates p73 transactivation.
abstract: The transcription factor p73 triggers developmental pathways and overlaps stress-induced p53 transcriptional pathways. How p53-family response elements determine and regulate transcriptional specificity remains an unsolved problem. In this work, we have determined the first crystal structures of p73 DNA-binding domain tetramer bound to response elements with spacers of different length. The structure and function of the adaptable tetramer are determined by the distance between two half-sites. The structures with zero and one base-pair spacers show compact p73 DNA-binding domain tetramers with large tetramerization interfaces; a two base-pair spacer results in DNA unwinding and a smaller tetramerization interface, whereas a four base-pair spacer hinders tetramerization. Functionally, p73 is more sensitive to spacer length than p53, with one base-pair spacer reducing 90% of transactivation activity and longer spacers reducing transactivation to basal levels. Our results establish the quaternary structure of the p73 DNA-binding domain required as a scaffold to promote transactivation.
authors.affiliation: Laboratory of Structural Biochemistry, Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive 0378, La Jolla, CA 92093, USA.
authors.forename: Abdul S
authors.initials: AS
authors.lastname: Ethayathulla
authors.forename: Pui-Wah
authors.initials: PW
authors.lastname: Tse
authors.forename: Paola
authors.initials: P
authors.lastname: Monti
authors.forename: Sonha
authors.initials: S
authors.lastname: Nguyen
authors.forename: Alberto
authors.initials: A
authors.lastname: Inga
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fronza
authors.forename: Hector
authors.initials: H
authors.lastname: Viadiu
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D020218:Response Elements / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013050:Spectrometry, Fluorescence; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D004247:DNA