Structure of the unphosphorylated STAT5a dimer.
STAT proteins have the function of signaling from the cell membrane into the nucleus, where they regulate gene transcription. Latent mammalian STAT proteins can form dimers in the cytoplasm even before receptor-mediated activation by specific tyrosine phosphorylation. Here we describe the 3.21-A crystal structure of an unphosphorylated STAT5a homodimer lacking the N-terminal domain as well as the C-terminal transactivation domain. The overall structure of this fragment is very similar to phosphorylated STATs. However, important differences exist in the dimerization mode. Although the interface between phosphorylated STATs is mediated by their Src-homology 2 domains, the unphosphorylated STAT5a fragment dimerizes in a completely different manner via interactions between their beta-barrel and four-helix bundle domains. The STAT4 N-terminal domain dimer can be docked onto this STAT5a core fragment dimer based on shape and charge complementarities. The separation of the dimeric arrangement, taking place upon activation and nuclear translocation of STAT5a, is demonstrated by fluorescence resonance energy transfer experiments in living cells.
Neculai
Dante
D
Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
Neculai
Ana Mirela
AM
Verrier
Sophie
S
Straub
Kenneth
K
Klumpp
Klaus
K
Pfitzner
Edith
E
Becker
Stefan
S
D000818:Animals; D001665:Binding Sites; D003460:Crystallization; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D024202:Electrophoretic Mobility Shift Assay; D031541:Fluorescence Resonance Energy Transfer; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology; D010766:Phosphorylation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D050799:STAT5 Transcription Factor / Q000737:chemistry* / Q000502:physiology; D018909:src Homology Domains
D010446:Peptide Fragments; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D004247:DNA