title: Phosphorylation of glucocorticoid receptor tau1c transactivation domain enhances binding to CREB binding protein (CBP) TAZ2.
abstract: The glucocorticoid receptor (GR) N-terminal domain (NTD) contains a transactivation domain (activation function 1; AF-1). GR AF-1 is phosphorylated, but effects of this modification upon AF-1 activity and cofactor recruitment are not completely clear. GR AF-1 activity is mostly confined to a short unstructured domain called tau1c (amino acids 187-244) that contains three phosphorylation sites and binds a short cysteine rich fragment (CH3) of the coactivator CREB binding protein (CBP). Since the CH3 domain overlaps the CBP transcriptional adaptor zinc binding (TAZ) 2 domain, implicated in phosphorylation dependent binding to other unstructured transcription factor domains, we set out to investigate whether GR interacts with TAZ2 and whether this binding event is modulated by phosphorylation. We find that GR tau1c is absolutely required for enhancement of GR function and GR/CBP association in cultured cells. Tau1c interacts with TAZ2 in vitro and peptide mapping reveals CBP binding determinants throughout tau1c. Phosphorylation at GR Ser203, not involved in transactivation, does not affect tau1c/TAZ2 interactions. However, phosphorylation at Ser211 and Ser226, markers of GR transcriptional activity, greatly enhances TAZ2 binding in a synergistic fashion. We propose that GR tau1c phosphorylation could promote CBP recruitment and enhance AF-1 activity.
authors.affiliation: Genomic Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA; Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77024, USA. Electronic address: chempilot@gmail.com.
authors.forename: Carl W
authors.initials: CW
authors.lastname: Carruthers
authors.affiliation: Genomic Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA. Electronic address: JHSuh@Houstonmethodist.org.
authors.forename: Ji Ho
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77024, USA. Electronic address: JGustafs@Central.UH.edu.
authors.forename: Jan-Ake
authors.initials: JA
authors.lastname: Gustafsson
authors.affiliation: Genomic Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA; Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77024, USA. Electronic address: pwebb@houstonmethodist.org.
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
mesh_terms: D000595:Amino Acid Sequence; D050882:CREB-Binding Protein / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011965:Receptors, Glucocorticoid / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
chemical_list: D010455:Peptides; D011965:Receptors, Glucocorticoid; D010768:Phosphoserine; D050882:CREB-Binding Protein; C494363:CREBBP protein, human
keywords: CREB binding protein; Coactivator; Gene expression; Glucocorticoid receptor; Phosphorylation; Protein biochemistry