Insight into the molecular recognition mechanism of the coactivator NCoA1 by STAT6

Crucial for immune and anti-inflammatory cellular responses, signal transducer and activator of transcription 6 (STAT6) regulates transcriptional activation in response to interleukin-4 and -13 -induced tyrosine phosphorylation by direct interaction with coactivators. The interaction of STAT6 with nuclear coactivator 1 (NCoA1) is mediated by a short region of the STAT6 transactivation domain that includes the motif LXXLL and interacts with the PAS-B domain of NCoA1. Despite the availability of an X-ray structure of the PAS-B domain/ Leu(794)-Gly(814)-STAT6 complex, the mechanistic details of this interaction are still poorly understood. Here, we determine the structure of the NCoA1(257–385)/STAT6(783–814) complex using Nuclear Magnetic Resonance (NMR) and X-ray crystallography. The STAT6(783–814) peptide binds with additional N-terminal amino acids to NCoA1(257–385), compared to the STAT6(794–814) peptide, explaining its higher affinity. Secondary and tertiary structures existing in the free peptide are more highly populated in the complex, suggesting binding by conformational selection.