Structure of the NCoA-1/SRC-1 PAS-B domain bound to the LXXLL motif of the STAT6 transactivation domain.
Signal transducer and activator of transcription 6 (STAT6) regulates transcriptional activation in response to interleukin-4 (IL-4) by direct interaction with coactivators. The CREB-binding protein (p300/CBP) and the nuclear coactivator 1 (NCoA-1), a member of the p160/steroid receptor coactivator family, bind independently to specific regions of the STAT6 transactivation domain and act as coactivators. The interaction between STAT6 and NCoA-1 is mediated by an LXXLL motif in the transactivation domain of STAT6. To define the mechanism of coactivator recognition, we determined the crystal structure of the NCoA-1 PAS-B domain in complex with the STAT6 LXXLL motif. The amphipathic, alpha-helical STAT6 LXXLL motif binds mostly through specific hydrophobic interactions to NCoA-1. A single amino acid of the NCoA-1 PAS-B domain establishes hydrophilic interactions with the STAT6 peptide. STAT6 interacts only with the PAS-B domain of NCoA-1 but not with the homologous regions of NCoA-2 and NCoA-3. The residues involved in binding the STAT6 peptide are strongly conserved between the different NCoA family members. Therefore surface complementarity between the hydrophobic faces of the STAT6 fragment and of the NCoA-1 PAS-B domain almost exclusively defines the binding specificity between the two proteins.
Razeto
Adelia
A
Department for NMR-based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany.
Ramakrishnan
Venkatesh
V
Litterst
Claudia M
CM
Giller
Karin
K
Griesinger
Christian
C
Carlomagno
Teresa
T
Lakomek
Nils
N
Heimburg
Thomas
T
Lodrini
Marco
M
Pfitzner
Edith
E
Becker
Stefan
S
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051548:Histone Acetyltransferases; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D056920:Nuclear Receptor Coactivator 1; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D050800:STAT6 Transcription Factor; D013379:Substrate Specificity; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D015533:Transcriptional Activation
D010446:Peptide Fragments; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1