title: A C-terminal inhibitory domain controls the activity of p63 by an intramolecular mechanism.
abstract: The human genome is far smaller than originally estimated, and one explanation is that alternative splicing creates greater proteomic complexity than a simple count of open reading frames would suggest. The p53 homologue p63, for example, is a tetrameric transcription factor implicated in epithelial development and expressed as at least six isoforms with widely differing transactivation potential. In particular, p63alpha isoforms contain a 27-kDa C-terminal region that drastically reduces their activity and is of clear biological importance, since patients with deletions in this C terminus have phenotypes very similar to patients with mutations in the DNA-binding domain. We have identified a novel domain within this C terminus that is necessary and sufficient for transcriptional inhibition and which acts by binding to a region in the N-terminal transactivation domain of p63 homologous to the MDM2 binding site in p53. Based on this mechanism, we provide a model that explains the transactivation potential of homo- and heterotetramers composed of different p63 isoforms and their effect on p53.
authors.affiliation: Graduate Group in Biophysics, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Zach
authors.initials: Z
authors.lastname: Serber
authors.forename: Helen C
authors.initials: HC
authors.lastname: Lai
authors.forename: Annie
authors.initials: A
authors.lastname: Yang
authors.forename: Horng D
authors.initials: HD
authors.lastname: Ou
authors.forename: Martina S
authors.initials: MS
authors.lastname: Sigal
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Kelly
authors.forename: Beatrice D
authors.initials: BD
authors.lastname: Darimont
authors.forename: Pascal H G
authors.initials: PH
authors.lastname: Duijf
authors.forename: Hans
authors.initials: H
authors.lastname: Van Bokhoven
authors.forename: Frank
authors.initials: F
authors.lastname: McKeon
authors.forename: Volker
authors.initials: V
authors.lastname: Dötsch
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D010455:Peptides; D010750:Phosphoproteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins